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TFEB regulates lysosomal positioning by modulating TMEM55B expression and JIP4 recruitment to lysosomes
Open accessAbstract
Lysosomal distribution is linked to the role of lysosomes in many cellular functions, including autophagosome degradation, cholesterol homeostasis, antigen presentation, and cell invasion. Alterations in lysosomal positioning contribute to different human pathologies, such as cancer, neurodegeneration, and lysosomal storage diseases. Here we report the identification of a novel mechanism of lysosomal trafficking regulation. We found that the lysosomal transmembrane protein TMEM55B recruits JIP4 to the lysosomal surface, inducing dynein-dependent transport of lysosomes toward the microtubules minus-end. TMEM55B overexpression causes lysosomes to collapse into the cell center, whereas depletion of either TMEM55B or JIP4 results in dispersion toward the cell periphery. TMEM55B levels are transcriptionally upregulated following TFEB and TFE3 activation by starvation or cholesterol-induced lysosomal stress. TMEM55B or JIP4 depletion abolishes starvation-induced retrograde lysosomal transport and prevents autophagosome–lysosome fusion. Overall our data suggest that the TFEB/TMEM55B/JIP4 pathway coordinates lysosome movement in response to a variety of stress conditions.
Overview
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Written from the paper’s full text.
TL;DR
The paper identifies TMEM55B as a lysosomal transmembrane protein that recruits JIP4 to lysosomes, promoting dynein-dependent retrograde transport and perinuclear lysosome clustering. TFEB/TFE3 upregulate TMEM55B under starvation or cholesterol stress, and TMEM55B/JIP4 depletion blocks starvation-induced lysosomal clustering and autophagosome–lysosome fusion.
Key findings
- TMEM55B overexpression clusters lysosomes in the cell center, while TMEM55B depletion causes over 80% reduction in TMEM55B mRNA/protein and shifts lysosomes toward the cell periphery; JIP4 depletion causes more than 60% of LAMP-1 signal to fall >15 μm from the nuclear rim.
- TMEM55B’s cytosolic domain recruits JIP4 to lysosomal membranes; in JIP4-depleted cells, GFP-TMEM55B fails to cluster lysosomes, with distal LAMP-1 signal >15 μm changing from 20% in control cells to more than 50%.
- Starvation increases TMEM55B mRNA/protein in a TFEB/TFE3-dependent manner; starvation-induced lysosomal clustering is reduced in TFEB-depleted cells and blocked by TMEM55B or JIP4 depletion, and JIP4 depletion reduces LC3II accumulation after EBSS plus bafilomycin.
- U18666A-induced cholesterol stress and NPC1 patient fibroblasts upregulate TMEM55B; JIP4 depletion reduces perinuclear clustering in NPC fibroblasts, and acute curcumin/NaAsO2 stress induces JIP4/p150Glued recruitment and lysosomal clustering via p38, not JNK or ERK.
Methods
- Cell culture and perturbations: ARPE-19, HeLa, U2OS, MEFs, and NPC1/control fibroblasts were subjected to siRNA/shRNA knockdown, adenoviral expression, rapamycin-induced dimerization, nocodazole, starvation, U18666A, curcumin/NaAsO2, and MAPK inhibitors.
- Imaging and quantification: immunofluorescence for LAMP-1, JIP4, p150Glued, and other markers; lysosome distribution measured by linear profile, radial profile, and cumulative intensity distribution; time-lapse confocal microscopy; statistics by two-tailed t-test or one-way ANOVA.
- Biochemical assays: qRT-PCR, immunoblotting, GFP/RFP pull-downs, mass spectrometry, subcellular fractionation, and phosphatidylinositol phosphatase assays including malachite green and PH-PLCD1 imaging.
Limitations
- The paper states that it remains to be determined whether TMEM55B functions as a mere JIP4 recruiter or also stimulates the interaction between JIP4 and the dynein–dynactin complex, and how the TMEM55B/JIP4 pathway works in conjunction with other retrograde pathways such as Rab7/RILP/ORP1L and MCOLN1/ALG-2.
- Evident from the text: mechanistic conclusions rely largely on cultured cell lines with overexpression, RNAi, and pharmacological stress, with no in vivo animal model or direct structural mapping of the TMEM55B–JIP4 interface presented.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
12 of 33 cited sources checked · 1 supported · 0 flagged · accuracy not yet measured
- Findingown data
The upregulation of TMEM55B induced by U18666A is significantly decreased in cells depleted of SREBF2.
“we observed that the upregulation of TMEM55B induced by U18666A was significantly decreased in cells depleted of SREBF2 (Fig. 7f)”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Medina et al. [48] Medina, M. W. et al. Transmembrane protein 55B is a novel regulator of cellular cholesterol metabolism. Arterioscler. Thromb. Vasc. Biol. 34, 1917–1923 (2014). source
Results section II reports that SREBF2 knockdown suppressed sterol-dependent upregulation of TMEM55B in HeLa cells. It does not report treatment with U18666A, so it does not establish the claim for that specific condition. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Findingown data
Depletion of either TMEM55B or JIP4 results in dispersion of lysosomes toward the cell periphery.
“depletion of either TMEM55B or JIP4 results in dispersion toward the cell periphery”
- Also stated in: § TMEM55B promotes lysosomal retrograde transport · plain
“In cells depleted of TMEM55B the distribution significantly shifted, showing a decrease in the concentration of LAMP-1-positive structures in the perinuclear region, concomitant with a distinct increase in the number of lysosomes localized towards the cell periphery”
Quote in the paperSubstantial claim - Also stated in: § TMEM55B promotes lysosomal retrograde transport · plain
- Findingown data
TMEM55B levels are transcriptionally upregulated following TFEB and TFE3 activation by starvation or cholesterol-induced lysosomal stress.
“TMEM55B levels are transcriptionally upregulated following TFEB and TFE3 activation by starvation or cholesterol-induced lysosomal stress.”
- Also stated in: § Introduction · plain
“Interestingly, TMEM55B is a target of TFEB and TFE3 and its mRNA and protein levels increase following TFEB/3 activation by starvation or cholesterol accumulation in lysosomes.”
Quote in the paperSubstantial claim- Rests on an assumption: Starvation activates TFEB and TFE3.
- Rests on an assumption: Cholesterol accumulation in lysosomes activates TFEB and TFE3.
- Also stated in: § Introduction · plain
- Findingown data
TMEM55B overexpression causes lysosomes to collapse into the cell center.
“TMEM55B overexpression causes lysosomes to collapse into the cell center”
- Also stated in: § TMEM55B promotes lysosomal retrograde transport · plain
“upon overexpression of GFP-TMEM55B, we observed a dramatic repositioning of lysosomes, changing from dispersed throughout the cell to tightly clustered in the cell center”
Quote in the paperSubstantial claim - Also stated in: § TMEM55B promotes lysosomal retrograde transport · plain
- Findingown data
TMEM55B-induced lysosome clustering is not cell-type specific, as shown in HeLa cells.
“Additionally, this lysosome clustering was not cell-type specific as evidenced by TMEM55B-induced lysosomal repositioning in HeLa cells (Fig. 1d).”
Quote in the paperNot a substantial claim
- Findingown data
Expression of GFP-TMEM55B in JIP4-depleted cells fails to induce clustering of lysosomes into the perinuclear region.
“expression of GFP-TMEM55B in cells depleted of JIP4 failed to induce clustering of lysosomes into the perinuclear region (Fig. 5d, bottom).”
Quote in the paperSubstantial claim - Findingown data
Disruption of the dynein-dynactin complex by P50-dynamitin overexpression completely blocks TMEM55B-induced lysosome clustering.
“disruption of the dynein–dynactin complex by overexpression of the dynactin complex subunit P50-dynamitin was sufficient to completely block TMEM55B-induced lysosome clustering (Fig. 2b).”
Quote in the paperSubstantial claim - Findingown data
Overexpression of GFP-TMEM55B results in accumulation of JIP4 on clustered lysosomes.
“overexpression of GFP-TMEM55B resulted in a very noticeable accumulation of JIP4 on clustered lysosomes (Fig. 4f)”
Quote in the paperSubstantial claim - Findingown data
Recruitment of RFP-FKBP-TMEM55B CD to mitochondria changes mitochondria morphology from dispersed, inter-connected membranes to a tight cluster in the cell center.
“Mitochondria expressing the targeting sequence AKAP1-FRB-GFP experienced dramatic changes in mitochondria morphology after recruitment of RFP-FKBP-TMEM55B CD to outer membranes, changing from dispersed, inter-connected membranes (Fig. 3c, top panel) to a tight cluster in the cell center (Fig. 3c, bottom panel).”
Quote in the paperSubstantial claim - Findingown data
The degree of lysosomal clustering following starvation is reduced in TFEB-depleted HeLa cells.
“Interestingly, the degree of lysosomal clustering following starvation was reduced in TFEB-depleted HeLa cells, suggesting that TFEB regulates lysosomal positioning in response to nutrient levels (Fig. 6h and Supplementary Fig. 9c).”
Quote in the paperSubstantial claim - Findingown data
Expression of recombinant JIP4 in JIP4-depleted cells rescues the accumulation of lysosomes in the cell periphery.
“expression of recombinant JIP4 in JIP4-depleted cells was sufficient to rescue the accumulation of lysosomes in the cell periphery (Supplementary Fig. 5b).”
Quote in the paperSubstantial claim - Findingown data
GFP-RILP expression is not capable of enriching recruitment of JIP4 to lysosome membranes, despite drastic lysosomal clustering.
“GFP-RILP expression was not capable of enriching recruitment of JIP4 to lysosome membranes, despite drastic lysosomal clustering (Supplementary Fig. 6c).”
Quote in the paperSubstantial claim - Findingown data
JIP4-dependent lysosomal retrograde transport in response to curcumin and NaAsO2 is confirmed in U2OS cells.
“JIP4-dependent lysosomal retrograde transport in response to curcumin and NaAsO2 was confirmed in U2OS cells (Supplemental Fig. 10b).”
Quote in the paperNot a substantial claim - Findingown data
Treatment of MEFs with curcumin results in obvious clustering of lysosomes as early as two hours after addition.
“Treatment of MEFs with curcumin, a pro-apoptotic agent that induces mitochondrial-dependent production of reactive oxygen species (ROS) and lysosomal destabilization51–54, resulted in a very obvious clustering of lysosomes as early as two hours following the addition of the drug (Fig. 8a).”
Quote in the paperSubstantial claim - Findingown data
Recruitment of RFP-FKBP-TMEM55B CD to lysosomes via rapamycin is sufficient to induce lysosome clustering in the perinuclear area.
“RFP-FKBP-TMEM55B CD was rapidly recruited to lysosomes upon addition of rapamycin; and this was sufficient to induce lysosomes clustering in the perinuclear area (Fig. 3a).”
Quote in the paperSubstantial claim - Findingown data
Curcumin causes rapid activation of different MAPKs, including p38, JNK, and Erk1/2.
“We found that curcumin caused a rapid activation of different MAPKs, including p38, JNK, and Erk1/2 (Fig. 8f); therefore, we assessed whether any of these kinases might contribute to changes in lysosomal distribution.”
Quote in the paperSubstantial claim - Findingown data
GFP-RILP expression in siControl-treated cells results in tight perinuclear clustering of LAMP-1 labeled lysosomes.
“GFP-RILP expression in siControl-treated cells resulted in tight perinuclear clustering of LAMP-1 labeled lysosomes (Fig. 5f, top).”
Quote in the paperSubstantial claim - Findingown data
The decrease in U18666A-induced TMEM55B upregulation is even more pronounced in cells depleted of SREBF2, TFEB, and TFE3.
“however, the decrease was even more pronounced in cells depleted of SREBF2, TFEB, and TFE3 (Fig. 7f)”
Quote in the paperSubstantial claim - Findingown data
TFEB and TFE3 control TMEM55B protein levels.
“We found that TFEB and TFE3 also control TMEM55B protein levels, indicating that these transcription factors play an active role in lysosomal positioning regulation.”
Quote in the paperSubstantial claim - Findingown data
TMEM55B RNA silencing reduces TMEM55B mRNA and protein levels by over 80%.
“TMEM55B RNA silencing was sufficient to induce over 80% reduction in TMEM55B mRNA and protein levels (Fig. 1e, f).”
Quote in the paperSubstantial claim - Findingown data
U18666A induces TFE3 activation in MEFs.
“Interestingly, U18666A induced TFE3 activation and TFEB/TFE3-dependent TMEM55B upregulation in MEFs, suggesting that the TFEB/TMEM55B/JIP4 pathway may also participate in the adaptation of lysosomal function and distribution in response to cholesterol (Fig. 7c, d).”
Quote in the paperSubstantial claim - Findingown data
JIP4 does not interact with GFP or GFP-LAMP1.
“JIP4 did not interact with GFP or GFP-LAMP1 (Fig. 4c)”
Quote in the paperNot a substantial claim - Findingown data
Increased lysosomal retrograde transport is observed when MEFs are treated with sodium arsenite (NaAsO2).
“Increased lysosomal retrograde transport was also observed when MEFs were treated with other ROS-generating compounds such as sodium arsenite (NaAsO2)55 (Supplementary Fig. 10a).”
Quote in the paperSubstantial claim - Findingown data
GFP-TMEM55B clusters lysosomes in cells depleted of ORP1L or RILP.
“GFP-TMEM55B clustered lysosomes in cells depleted of ORP1L or RILP (Supplementary Fig. 6a).”
Quote in the paperSubstantial claim - Findingown data
Treatment of cells with compounds that generate oxidative stress and lysosomal damage results in rapid and pronounced redistribution of lysosomes toward the cell center.
“We noticed that treatment of cells with different compounds known to generate oxidative stress and lysosomal damage resulted in a rapid and pronounced redistribution of lysosomes toward the cell center (Fig. 8).”
Quote in the paperSubstantial claim - Findingown data
Efficient JIP4 depletion was confirmed by western blot.
“Efficient JIP4 depletion was confirmed by western blot (Fig. 5c).”
Quote in the paperSubstantial claim - Findingown data
TMEM55B is retained at the plasma membrane when endocytosis is inhibited by a dominant-negative dynamin mutant.
“This observation was supported by the retention of TMEM55B at the plasma membrane when endocytosis was inhibited by overexpression of a dominant-negative mutant of dynamin (GFP-Dynamin-K44A) (Supplementary Fig. 2c).”
Quote in the paperSubstantial claim - Findingown data
GFP-RILP is still capable of inducing perinuclear accumulation of lysosomes in cells depleted of either TMEM55B or JIP4.
“GFP-RILP was still capable of inducing perinuclear accumulation of lysosomes in cells depleted of either TMEM55B or JIP4 (Fig. 5f, middle and bottom)”
Quote in the paperSubstantial claim - Findingown data
Expression of TMEM55A does not readily alter lysosome positioning.
“expression of TMEM55A did not readily alter lysosome positioning (Supplementary Fig. 4b)”
Quote in the paperSubstantial claim - Findingown data
The block in lysosome clustering by nocodazole is rapidly reversed upon nocodazole washout.
“The block in lysosome clustering was rapidly reversed upon nocodazole washout, demonstrating the dynamic role of TMEM55B in directing lysosomes towards the cell center (Fig. 2a, bottom panels).”
Quote in the paperSubstantial claim - Findingown data
Increased JIP4 and p150Glued recruitment to membranes occurs upon TMEM55B overexpression, as observed by subcellular fractionation.
“Increased JIP4 and p150Glued recruitment to membranes upon TMEM55B overexpression was also observed by subcellular fractionation (Supplementary Fig. 4c, d).”
Quote in the paperSubstantial claim - Findingown data
Recruitment of TMEM55B CD to the plasma membrane via rapamycin-induced dimerization with Lyn11-FRB-iRFP does not change PtdIns-4,5-P2 levels.
“recruitment of TMEM55B CD to the plasma membrane via rapamycin-induced dimerization with Lyn11-FRB-iRFP did not change PtdIns-4,5-P2 levels (Supplementary Fig. 8c, d).”
Quote in the paperSubstantial claim - Findingown data
U18666A induces TFEB/TFE3-dependent TMEM55B upregulation in MEFs.
“Interestingly, U18666A induced TFE3 activation and TFEB/TFE3-dependent TMEM55B upregulation in MEFs, suggesting that the TFEB/TMEM55B/JIP4 pathway may also participate in the adaptation of lysosomal function and distribution in response to cholesterol (Fig. 7c, d).”
Quote in the paperSubstantial claim - Findingown data
TMEM55B does not bind endogenous or recombinant LAMP1.
“TMEM55B did not bind endogenous or recombinant LAMP1 (Fig. 4d, e)”
Quote in the paperNot a substantial claim - Findingown data
The lack of co-localization of TMEM55B CD and TMEM55B TM with LAMP-1 is consistent with their inability to induce lysosomal clustering.
“The lack of co-localization of TMEM55B CD and TMEM55B TM with LAMP-1 was consistent with their inability to induce lysosomal clustering (Supplementary Fig. 2a).”
Quote in the paperSubstantial claim - Findingreasoning
TMEM55B silencing or overexpression perturbs the balance between dynein and kinesin, resulting in transport of lysosomes toward the periphery or the cell center, respectively.
“Accordingly, the balance between dynein and kinesin is perturbed by TMEM55B silencing or overexpression, resulting in transport of lysosomes toward the periphery or the cell center, respectively.”
Quote in the paperSubstantial claim- Rests on an assumption: Lysosomes undergo bidirectional transport along microtubules through the opposite activities of dynein and kinesins.
- Findingown data
JIP4 is a major interacting protein of TMEM55B CD.
“we identified the dynein scaffold JIP4 as a major interacting protein of TMEM55B CD (Supplementary Fig. 4a).”
Quote in the paperSubstantial claim - Findingown data
TMEM55A mRNA levels do not respond to starvation in MEFs.
“In contrast, TMEM55A mRNA levels did not respond to starvation (Fig. 6g).”
Quote in the paperNot a substantial claim - Findingown data
Intact microtubules are required for TMEM55B-dependent lysosome movement.
“depolarization of microtubules with nocodazole prevented perinuclear accumulation of lysosomes in TMEM55B-expresssing cells (Fig. 2a, top panel), confirming that intact microtubules were indeed required for TMEM55B-dependent lysosome movement.”
Quote in the paperSubstantial claim - Findingown data
TMEM55B protein levels increase in HeLa cells incubated in EBSS for different periods.
“An increase in TMEM55B protein levels was also observed in HeLa cells incubated in EBSS for different periods of time (Supplementary Fig. 9b).”
Quote in the paperSubstantial claim - Findingown data
The percent of LAMP-1-positive structures in the distal region (>15 μm from nuclear rim) changes from 20% in control cells to more than 50% in JIP4-depleted cells.
“the percent of LAMP-1-positive structures in the distal region of the cell (>15 μm from the nuclear rim) changed from 20% in control cells to more than 50% in JIP4-depleted cells (Fig. 5e).”
Quote in the paperSubstantial claim - Findingreasoning
Autophagy flux is impaired in JIP4-depleted cells.
“Accordingly, autophagy flux was impaired in JIP4-depleted cells.”
Quote in the paperSubstantial claim - Findingown data
Depletion of TMEM55B, or more dramatically JIP4, prevents U18666A-mediated lysosomal clustering.
“Accordingly, depletion of TMEM55B, or more dramatically JIP4, prevented U18666A-mediated lysosomal clustering without affecting U18666A-induced lysosomal enlargement (Fig. 7e and Supplementary Fig. 9e).”
Quote in the paperSubstantial claim - Findingown data
Depletion of TMEM55B or JIP4 does not affect U18666A-induced lysosomal enlargement.
“Accordingly, depletion of TMEM55B, or more dramatically JIP4, prevented U18666A-mediated lysosomal clustering without affecting U18666A-induced lysosomal enlargement (Fig. 7e and Supplementary Fig. 9e).”
Quote in the paperSubstantial claim - Findingown data
Autophagy flux is significantly impaired in TMEM55-depleted cells.
“Autophagy flux was also significantly impaired in TMEM55-depleted cells (Supplementary Fig. 9d).”
Quote in the paperSubstantial claim - Findingown data
JIP4 depletion reduces perinuclear clustering of lysosomes in NPC fibroblasts.
“Similar to our observations in U18666A-treated cells, JIP4 depletion reduced perinuclear clustering of lysosomes in NPC fibroblasts (Fig. 7h, Supplementary Fig. 9f, g), suggesting that alterations in the TMEM55B/JIP4 pathway may contribute to the pathology of the disease.”
Quote in the paperSubstantial claim - Findingown data
TMEM55B induces efficient perinuclear accumulation of lysosomes in MCOLN1-depleted cells.
“we found that TMEM55B induced efficient perinuclear accumulation of lysosomes in MCOLN1-depleted cells (Supplementary Fig. 7).”
Quote in the paperSubstantial claim - Findingown data
Depletion of either TMEM55B or JIP4 is sufficient to block starvation-induced lysosomal clustering.
“Moreover, depletion of either TMEM55B or JIP4 was sufficient to block starvation-induced lysosomal clustering (Fig. 6i, j).”
Quote in the paperSubstantial claim - Findingown data
Recruitment of RFP-FKBP-TMEM55B CD to Mreg-positive vesicles causes dramatic clustering of late endosomes/lysosomes in the cell center.
“RFP-FKBP-TMEM55B CD was efficiently recruited to Mreg-positive vesicles following rapamycin treatment, causing dramatic clustering of late endosomes/lysosomes in the cell center (Fig. 3b).”
Quote in the paperSubstantial claim - Findingown data
Curcumin induces robust recruitment of JIP4 and the dynactin subunit p150Glued to lysosomal membranes.
“Curcumin induced robust recruitment of JIP4 and the dynactin subunit p150Glued to lysosomal membranes (Fig. 8b, c), suggesting that TMEM55B/JIP4 complex may regulate lysosomal retrograde transport under acute stress conditions.”
Quote in the paperSubstantial claim - Findingown data
Starvation in EBSS significantly increases TMEM55B mRNA levels in MEFs.
“Starvation also significantly increased TMEM55B mRNA levels, and this increase was TFEB/TFE3-dependent since it was not observed in TFEB/TFE3 double knockout MEFs (Fig. 6f).”
Quote in the paperSubstantial claim - Findingown data
Sterol depletion by lipoprotein-depleted serum and statins causes significant TMEM55B upregulation at both mRNA and protein levels in HeLa cells.
“In agreement with this report, we found that in HeLa cells, sterol depletion by treatment with a combination of lipo-protein depleted serum and statins caused a significant TMEM55B upregulation both to the mRNA and protein levels (Fig. 7a, b).”
Quote in the paperSubstantial claim - Findingreasoning
LC3II levels following bafilomycin treatment are significantly reduced in JIP4-depleted cells.
“In contrast, LC3II levels following bafilomycin treatment were significantly reduced in JIP4-depleted cells (Fig. 6k, l) since autophagosomes were unable to fuse with peripheral lysosomes (Fig. 6m).”
Quote in the paperSubstantial claim - Findingown data
Treatment with U18666A upregulates TMEM55B.
“Upregulation of TMEM55B was also observed following treatment with U18666A (Fig. 7a, b), an amphipathic steroid which blocks cholesterol exit from late endosomes/lysosomes, inducing lysosomal stress49.”
Quote in the paperSubstantial claim - Findingown data
The lysosomal protein TMEM55B recruits JIP4 to lysosomal membranes to promote dynein-dependent retrograde transport.
“We found that the lysosomal protein TMEM55B recruits JIP4 to lysosomal membranes to promote dynein-dependent retrograde transport (Fig. 7i).”
Quote in the paperSubstantial claim - Findingown data
Curcumin- and NaAsO2-induced lysosomal clustering is inhibited in JIP4-depleted MEFs.
“Accordingly, curcumin and NaAsO2-induced lysosomal clustering was inhibited in JIP4-depleted MEFs (Fig. 8d and Supplementary Fig. 10a).”
Quote in the paperSubstantial claim - Findingown data
TMEM55B protein levels are upregulated in NPC1 patient fibroblasts compared with control fibroblasts.
“Analysis of control (clone GM25445) and NPC-1 fibroblasts (clones GM25439 and GM03123) confirmed that TMEM55B protein levels were upregulated in patient cells (Fig. 7g).”
Quote in the paperSubstantial claim - Interpretationown data
The TFEB/TMEM55B/JIP4 pathway coordinates lysosome movement in response to a variety of stress conditions.
“Overall our data suggest that the TFEB/TMEM55B/JIP4 pathway coordinates lysosome movement in response to a variety of stress conditions.”
Quote in the paperSubstantial claim- Rests on an assumption: Starvation activates TFEB and TFE3.
- Rests on an assumption: Cholesterol accumulation in lysosomes activates TFEB and TFE3.
- Interpretationown data
TMEM55B recruits JIP4 to the lysosomal surface, inducing dynein-dependent transport of lysosomes toward the microtubule minus-end.
“We found that the lysosomal transmembrane protein TMEM55B recruits JIP4 to the lysosomal surface, inducing dynein-dependent transport of lysosomes toward the microtubules minus-end.”
- Also stated in: § Introduction · plain
“We found that the lysosomal protein TMEM55B interacts and recruits the dynein adaptor JIP4 to lysosomal membranes, thus inducing retrograde transport of lysosomes along microtubules.”
Quote in the paperSubstantial claim- Rests on an assumption: JIP4 is a dynein adaptor/scaffold that links cargo to dynein–dynactin.
- Also stated in: § Introduction · plain
- Interpretationown data
TMEM55B recruits the motor adapter JIP4 to bring dynein-dynactin to lysosomal membranes.
“Altogether, our results suggest that TMEM55B recruits the motor adapter JIP4 to bring dynein–dynactin to lysosomal membranes.”
Quote in the paperSubstantial claim- Rests on an assumption: JIP4 is a dynein adaptor/scaffold that links cargo to dynein–dynactin.
- Interpretationown data
SREBF2, TFEB, and TFE3 contribute to regulate TMEM55B levels in response to changes in cellular cholesterol homeostasis.
“suggesting that the three transcription factors contribute to regulate TMEM55B levels in response to changes in cellular cholesterol homeostasis.”
Quote in the paperSubstantial claim - Interpretationown data
TMEM55B plays a role in determining lysosome positioning.
“Based on these results, we concluded that TMEM55B plays a role in determining lysosome positioning.”
Quote in the paperSubstantial claim - Interpretationreasoning
TFEB/3, TMEM55B, and JIP4 participate in the cholesterol-dependent distribution of lysosomes.
“TFEB/3, TMEM55B, and JIP4 also participate in the cholesterol-dependent distribution of lysosomes.”
Quote in the paperSubstantial claim - Interpretationown data
The TMEM55B/JIP4 complex may regulate lysosomal retrograde transport under acute stress conditions.
“Curcumin induced robust recruitment of JIP4 and the dynactin subunit p150Glued to lysosomal membranes (Fig. 8b, c), suggesting that TMEM55B/JIP4 complex may regulate lysosomal retrograde transport under acute stress conditions.”
Quote in the paperSubstantial claim - Interpretationown data
TMEM55B might undergo post-translational modifications in response to acute stress.
“Treatment of U2OS cells with NaAsO2 resulted in a clear shift in TMEM55B electrophoretic mobility, as well as an increase in TMEM55B dimerization (Fig. 8e), suggesting that TMEM55B might undergo post-translational modifications in response to acute stress.”
Quote in the paperNot a substantial claim - Interpretationown data
The TMEM55B/JIP4 complex links signaling to rapid changes in lysosomal positioning in response to cellular damage.
“Altogether, our data suggest that the TMEM55B/JIP4 complex links signaling to rapid changes in lysosomal positioning in response to cellular damage.”
Quote in the paperSubstantial claim - Interpretationown data
TMEM55B regulation, both at the transcriptional and post-translational levels, may help coordinate the lysosomal response to different types of stress.
“Moreover, TMEM55B regulation, both to the transcriptional and post-translational levels, may help coordinating the lysosomal response to different types of stress.”
Quote in the paperNot a substantial claim - Interpretationown data
TMEM55B promotes microtubule minus-end organelle trafficking.
“We observed extensive co-localization of α-tubulin with mitochondria following RFP-FKBP-TMEM55B CD recruitment (Supplementary Fig. 3b), further suggesting that TMEM55B promotes microtubule minus-end organelle trafficking.”
Quote in the paperSubstantial claim - Interpretationown data
JIP4 is required to link TMEM55B-positive lysosomes to the dynein-dynactin complex.
“Therefore, JIP4 is required to link TMEM55B-positive lysosomes to the dynein–dynactin complex.”
Quote in the paperSubstantial claim- Rests on an assumption: JIP4 is a dynein adaptor/scaffold that links cargo to dynein–dynactin.
- Interpretationown data
TFEB regulates lysosomal positioning in response to nutrient levels.
“Interestingly, the degree of lysosomal clustering following starvation was reduced in TFEB-depleted HeLa cells, suggesting that TFEB regulates lysosomal positioning in response to nutrient levels (Fig. 6h and Supplementary Fig. 9c).”
Quote in the paperSubstantial claim - Interpretationown data
p38 has a novel and unexpected role in retrograde organelle transport.
“Interestingly, lysosomal clustering and JIP4 recruitment to lysosomes was prevented by incubation with p38 inhibitors, but not JNK or Erk1/2 inhibitors (Fig. 8g, h), thus revealing a novel and unexpected role of p38 in retrograde organelle transport.”
Quote in the paperSubstantial claim - Interpretationown data
The TFEB/TMEM55B/JIP4 pathway is involved in mediating nutrient-dependent trafficking of lysosomes to stimulate efficient autophagic flux.
“These results indicate that the TFEB/TMEM55B/JIP4 pathway is involved in mediating nutrient-dependent trafficking of lysosomes to stimulate efficient autophagic flux.”
Quote in the paperSubstantial claim- Rests on an assumption: Lysosome transport to the perinuclear region following starvation is critical to facilitate autophagosome–lysosome interactions and controls the rate of autophagosome degradation.
- Premisecitation
TMEM55B is a target of TFEB and TFE3.
“TMEM55B is a target of TFEB and TFE3”
- Also stated in: § TMEM55B promotes lysosomal retrograde transport · hedged
“ChIP-seq analysis identified TMEM55B as a putative TFE3 target both in RAW 264.7 macrophages and MEFs5,6.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [5] Pastore, N. et al. TFEB and TFE3 cooperate in the regulation of the innate immune response in activated macrophages. Autophagy 12, 1240–1258 (2016). source
- cites [6] Martina, J. A., Diab, H. I., Brady, O. A. & Puertollano, R. TFEB and TFE3 are novel components of the integrated stress response. EMBO J. 35, 479–495 (2016). source
- Also stated in: § TMEM55B promotes lysosomal retrograde transport · hedged
- Interpretationown data
In JIP4-depleted cells, autophagosomes are unable to fuse with peripheral lysosomes.
“In contrast, LC3II levels following bafilomycin treatment were significantly reduced in JIP4-depleted cells (Fig. 6k, l) since autophagosomes were unable to fuse with peripheral lysosomes (Fig. 6m).”
Quote in the paperSubstantial claim - Interpretationown data
The TFEB/TMEM55B/JIP4 pathway may participate in the adaptation of lysosomal function and distribution in response to cholesterol.
“Interestingly, U18666A induced TFE3 activation and TFEB/TFE3-dependent TMEM55B upregulation in MEFs, suggesting that the TFEB/TMEM55B/JIP4 pathway may also participate in the adaptation of lysosomal function and distribution in response to cholesterol (Fig. 7c, d).”
Quote in the paperSubstantial claim - Interpretationown data
Any lipid phosphatase activity of TMEM55B or TMEM55A is exceptionally weak and unlikely to constitute the main function of these proteins.
“Therefore, it seems that any lipid phosphatase activity of TMEM55B or TMEM55A is exceptionally weak, and unlikely to constitute the main function of these proteins.”
Quote in the paperNot a substantial claim - Interpretationown data
Alterations in the TMEM55B/JIP4 pathway may contribute to the pathology of NPC disease.
“Similar to our observations in U18666A-treated cells, JIP4 depletion reduced perinuclear clustering of lysosomes in NPC fibroblasts (Fig. 7h, Supplementary Fig. 9f, g), suggesting that alterations in the TMEM55B/JIP4 pathway may contribute to the pathology of the disease.”
Quote in the paperSubstantial claim- Rests on an assumption: In NPC1 and other lysosomal diseases, persistent accumulation of cholesterol in late endosomes/lysosomes leads to aberrant lysosomal clustering in the cell center.
- Interpretationreasoning
TFEB and TFE3 play an active role in lysosomal positioning regulation.
“We found that TFEB and TFE3 also control TMEM55B protein levels, indicating that these transcription factors play an active role in lysosomal positioning regulation.”
Quote in the paperSubstantial claim - Interpretationown data
The Rab7/RILP/ORP1L and MCOLN1-ALG2 pathways function independently of the TMEM55B/JIP4 pathway for recruiting dynein to late endosomes/lysosomes to promote retrograde trafficking.
“Altogether, our results indicate that the Rab7/RILP/ORP1L and MCOLN1–ALG2 pathways function independently of our newly described TMEM55B/JIP4 pathway for recruiting dynein to late endosomes/lysosomes to promote retrograde trafficking.”
Quote in the paperSubstantial claim - Interpretationown data
Regulation of TMEM55B expression in response to changes in nutrient and cholesterol levels is critical to ensure proper cellular homeostasis.
“In summary, we conclude that the regulation of TMEM55B expression in response to changes in nutrient and cholesterol levels is critical to ensure proper cellular homeostasis (Fig. 7i).”
Quote in the paperSubstantial claim - Interpretationown data
TMEM55B drives JIP4 membrane recruitment.
“suggesting that TMEM55B drives JIP4 membrane recruitment.”
Quote in the paperSubstantial claim - Interpretationown data
The TMEM55B/JIP4 complex may be part of a surveillance system which allows rapid changes in lysosomal positioning in response to cellular damage.
“Our data suggest that the TMEM55B/JIP4 complex may be part of a surveillance system which allows rapid changes in lysosomal positioning in response to cellular damage.”
Quote in the paperSubstantial claim - Interpretationreasoning
TMEM55B functions as a linker between lysosomes and microtubules.
“Therefore, TMEM55B functions as a linker between lysosomes and microtubules.”
Quote in the paperSubstantial claim - Interpretationown data
RILP and TMEM55B function independently of one another.
“suggesting that RILP and TMEM55B function independently of one another.”
Quote in the paperSubstantial claim
- Probably not a substantial claim. 24
- It may state two separate claims as one. 32
- The quote only partly states this claim. 1
Probably not a substantial claim.
PremisecitationUnder starvation conditions, autophagosomes and lysosomes move toward the cell center, facilitating fusion and degradation of autophagosomal content.
“under starvation conditions, autophagosomes and lysosomes move toward the cell center, facilitating the fusion between both organelles and degradation of the autophagosomal content9,10.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [9] Kimura, S., Noda, T. & Yoshimori, T. Dynein-dependent movement of autophagosomes mediates efficient encounters with lysosomes. Cell Struct. Funct. 33, 109–122 (2008). source
The sections “Autophagosomes move toward the cell center” and “Significance of the rapid vectorial movement for autophagy” support movement of autophagosomes toward centrally clustered lysosomes and its role in efficient targeting. But “Anti-LC3 antibody microinjection inhibits autophagosome movement” says lysosome localization did not significantly change under starvation; the paper does not support the claim that lysosomes also move toward the cell center under those conditions. Page numbers are unavailable in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measured - cites [10] Korolchuk, V. I. et al. Lysosomal positioning coordinates cellular nutrient responses. Nat. Cell Biol. 13, 453–460 (2011). source
Probably not a substantial claim.
PremisecitationRedistribution of lysosomes toward the cell periphery is critical for cancer growth, invasion and metastasis.
“Redistribution of lysosomes toward the cell periphery is critical for cancer growth, invasion and metastasis.”
Quote in the paperSubstantial claim1 of 4 sources checked- cites [11] Nishimura, Y., Itoh, K., Yoshioka, K., Tokuda, K. & Himeno, M. Overexpression of ROCK in human breast cancer cells: evidence that ROCK activity mediates intracellular membrane traffic of lysosomes. Pathol. Oncol. Res. 9, 83–95 (2003). source
- cites [12] Macpherson, I. R. et al. CLIC3 controls recycling of late endosomal MT1-MMP and dictates invasion and metastasis in breast cancer. J. Cell Sci. 127, 3893–3901 (2014). source
- cites [13] Marchesin, V. et al. ARF6-JIP3/4 regulate endosomal tubules for MT1-MMP exocytosis in cancer invasion. J. Cell Biol. 211, 339–358 (2015). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [14] Dykes, S. S. et al. The Arf-like GTPase Arl8b is essential for three-dimensional invasive growth of prostate cancer in vitro and xenograft formation and growth in vivo. Oncotarget 7, 31037–31052 (2016). source
The Introduction says peripheral lysosome trafficking facilitates protease secretion and invasion, and the Discussion links it to invasive growth and, ultimately, metastasis (pages not provided). But the Discussion distinguishes this trafficking role from Arl8b’s metabolic role in tumor growth; the paper does not establish that peripheral redistribution itself is critical for cancer growth or directly demonstrate metastasis. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationKinesin-dependent tubulation of lysosomes is required for efficient MHCII-mediated antigen presentation in dendritic cells.
“kinesin-dependent tubulation of lysosomes is required for efficient MHCII-mediated antigen presentation in dendritic cells16–18.”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [16] Chow, A., Toomre, D., Garrett, W. & Mellman, I. Dendritic cell maturation triggers retrograde MHC class II transport from lysosomes to the plasma membrane. Nature 418, 988–994 (2002). source
- cites [17] Vyas, J. M. et al. Tubulation of class II MHC compartments is microtubule dependent and involves multiple endolysosomal membrane proteins in primary dendritic cells. J. Immunol. 178, 7199–7210 (2007). source
The Discussion (page unavailable) reports that endolysosomal tubules carry class II MHC molecules toward the cell surface and depend on microtubules. It says kinesin is a possible motor but that direct evidence is lacking. The paper also does not establish that tubulation is required for efficient MHCII-mediated antigen presentation. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [18] Mrakovic, A., Kay, J. G., Furuya, W., Brumell, J. H. & Botelho, R. J. Rab7 and Arl8 GTPases are necessary for lysosome tubulation in macrophages. Traffic 13, 1667–1679 (2012). source
The paper reports in “Dynein and kinesin are required for lysosome tubulation” (page unavailable) that disrupting kinesin reduced tubular lysosomes in macrophages. Its Discussion (page unavailable) says tubular MHCII compartments in dendritic cells have been proposed to deliver antigen-loaded MHCII to immune synapses. It does not establish that kinesin-dependent tubulation is required for efficient antigen presentation in dendritic cells. (LLM, conf=0.89)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationLAMP-1 and LAMP-2 promote coupling of lysosomes to dynein-dynactin.
“LAMP-1 and LAMP-2 promote coupling of lysosomes to dynein–dynactin26,27”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [26] Huynh, K. K. et al. LAMP proteins are required for fusion of lysosomes with phagosomes. EMBO J. 26, 313–324 (2007). source
The Distribution and motility section reports reduced dynein-mediated lysosome transport in cells lacking LAMP-1 and LAMP-2. The Discussion proposes that LAMPs help lysosomes associate with dynein–dynactin, but says the physical link is unclear; it does not establish coupling as a demonstrated mechanism. No page numbers are available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [27] Krzewski, K., Gil-Krzewska, A., Nguyen, V., Peruzzi, G. & Coligan, J. E. LAMP1/CD107a is required for efficient perforin delivery to lytic granules and NK-cell cytotoxicity. Blood 121, 4672–4683 (2013). source
It may state two separate claims as one.
Findingown dataWe could not detect robust hydrolysis of PtdIns-4,5-P2 by either TMEM55, though we could detect hydrolysis by SHIP2.
“We could not detect robust hydrolysis of PtdIns-4,5-P2 by either TMEM55, though we could detect hydrolysis by SHIP2, despite the fact that this enzyme has by far the weakest activity against this substrate of the 5-phosphatases44 (Supplementary Fig. 8e).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [44] Tresaugues, L. et al. Structural basis for phosphoinositide substrate recognition, catalysis, and membrane interactions in human inositol polyphosphate 5-phosphatases. Structure 22, 744–755 (2014). source
The Results (page unavailable) report that SHIP2 had low activity relative to the other 5-phosphatases assayed, supporting the comparison attached to citation 44. The study tested soluble, short-chain phosphoinositide analogs and the isolated SHIP2 catalytic domain; it does not establish that intact SHIP2 has the weakest activity against native PtdIns(4,5)P2 among all 5-phosphatases. The TMEM55 observations are the citing authors’ own results, not a finding attributed to this source. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationRetrograde movement is regulated by Rab7 and its effector RILP, which recruits dynein to lysosomes.
“Retrograde movement is regulated by Rab7 and its effector RILP. RILP interacts with the p150-glued subunit of dynactin, thus recruiting the minus-end-directed microtubule motor dynein to lysosomes23–25.”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [23] Cantalupo, G., Alifano, P., Roberti, V., Bruni, C. B. & Bucci, C. Rab-interacting lysosomal protein (RILP): the Rab7 effector required for transport to lysosomes. EMBO J. 20, 683–693 (2001). source
The Abstract and Discussion identify RILP as a Rab7 effector involved in late endocytic transport and lysosomal organization. The Discussion only proposes that RILP might link Rab7-containing organelles to a motor complex; it does not establish that RILP binds p150-Glued or recruits dynein to lysosomes. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [24] Johansson, M. et al. Activation of endosomal dynein motors by stepwise assembly of Rab7-RILP-p150Glued, ORP1L, and the receptor betalll spectrin. J. Cell Biol. 176, 459–471 (2007). source
The Discussion states that Rab7 acts through RILP to recruit dynein–dynactin for minus-end transport, and that RILP directly binds dynactin’s p150Glued subunit. The paper demonstrates this recruitment on late endosomes (LEs), rather than specifically on lysosomes; it also says ORP1L and βIII spectrin are needed for transport after recruitment. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [25] Jordens, I. et al. The Rab7 effector protein RILP controls lysosomal transport by inducing the recruitment of dynein-dynactin motors. Curr. Biol. 11, 1680–1685 (2001). source
The supplied passages report that Rab7-associated RILP recruits dynein–dynactin complexes to late endosomes and lysosomes, producing minus-end-directed transport. They also report recruitment of p150glued, but the cited sentence’s claim that RILP interacts with that subunit is not established: the paper says its assays revealed no direct interaction with motor-complex subunits. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationOverexpression of Rab34, Rab36, Rabring7, or Rapsyn causes clustering of lysosomes in the perinuclear area.
“overexpression of Rab34, Rab36, Rabring7, or Rapsyn causes clustering of lysosomes in the perinuclear area.”
Quote in the paperNot a substantial claim1 of 4 sources checked- cites [30] Chen, L., Hu, J., Yun, Y. & Wang, T. Rab36 regulates the spatial distribution of late endosomes and lysosomes through a similar mechanism to Rab34. Mol. Membr. Biol. 27, 23–30 (2010). source
The Abstract and Figure 3 caption (page not provided) report that Rab36 overexpression clusters lysosomes around the Golgi in the perinuclear region. The Introduction describes Rab34 as regulating lysosome distribution near the Golgi, and Figure 3 compares Rab34 overexpression with Rab36. Our copy does not address Rabring7 or Rapsyn, so it does not support the full list. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [31] Wang, T. & Hong, W. Interorganellar regulation of lysosome positioning by the Golgi apparatus through Rab34 interaction with Rab-interacting lysosomal protein. Mol. Biol. Cell 13, 4317–4332 (2002). source
- cites [32] Mizuno, K., Kitamura, A. & Sasaki, T. Rabring7, a novel Rab7 target protein with a RING finger motif. Mol. Biol. Cell 14, 3741–3752 (2003). source
- cites [33] Aittaleb, M., Chen, P. J. & Akaaboune, M. Failure of lysosome clustering and positioning in the juxtanuclear region in cells deficient in rapsyn. J. Cell Sci. 128, 3744–3756 (2015). source
It may state two separate claims as one.
Findingown dataTMEM55B or JIP4 depletion abolishes starvation-induced retrograde lysosomal transport and prevents autophagosome-lysosome fusion.
“TMEM55B or JIP4 depletion abolishes starvation-induced retrograde lysosomal transport and prevents autophagosome–lysosome fusion.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown dataNutrient deprivation causes a modest but statistically significant increase in JIP4 mRNA levels.
“A modest, although statistically significant, increase in JIP4 mRNA levels was also observed in nutrient-deprived cells (Supplementary Fig. 9a).”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
FindingcitationRecruitment of INPP5E to the cell surface induces a nearly complete loss of plasma membrane PtdIns-4,5-P2.
“recruitment of INPP5E to the cell surface, which was used as a positive control43, induced a nearly complete loss of plasma membrane PtdIns-4,5-P2 (Supplementary Fig. 8c, d).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [43] Varnai, P., Thyagarajan, B., Rohacs, T. & Balla, T. Rapidly inducible changes in phosphatidylinositol 4,5-bisphosphate levels influence multiple regulatory functions of the lipid in intact living cells. J. Cell Biol. 175, 377–382 (2006). source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
Findingown dataInduction of acute stress by treatment with NaAsO2 or curcumin results in post-transcriptional regulation of TMEM55B, increased JIP4 and p150Glued recruitment to lysosomes, and rapid lysosomal retrograde transport via a mechanism that requires JIP4 and p38 activation.
“In agreement with this idea, we found that induction of acute stress by treatment with NaAsO2 or curcumin resulted in post-transcriptional regulation of TMEM55B, increased JIP4 and p150Glued recruitment to lysosomes, and rapid lysosomal retrograde transport via a mechanism that required JIP4 and p38 activation.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown dataIncubation of MEFs in EBSS causes significant MCOLN1 upregulation.
“Accordingly, incubation of MEFs in EBSS (starvation medium) caused significant MCOLN1 upregulation, a lysosomal protein and TFEB/TFE3 target used in this experiment as a positive control (Fig. 6e).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataGolgi morphology and early endosome distribution are unaffected in cells depleted of either TMEM55B or JIP4.
“Golgi morphology and early endosome distribution was unaffected in cells depleted of either TMEM55B or JIP4 (Supplementary Fig. 5c, d), demonstrating the specificity of TMEM55B/JIP4 in regulating late-endosome/lysosome trafficking.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataTMEM55B depletion causes a significant shift in lysosome distribution, decreasing perinuclear LAMP-1 structures and increasing lysosomes at the cell periphery.
“In cells depleted of TMEM55B the distribution significantly shifted, showing a decrease in the concentration of LAMP-1-positive structures in the perinuclear region, concomitant with a distinct increase in the number of lysosomes localized towards the cell periphery (Fig. 1g, h).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIn control RNAi-treated cells, lysosomes are broadly distributed throughout the cell with a slight concentration in the perinuclear region.
“In control RNAi-treated cells, lysosomes were broadly distributed throughout the cell, with a slight concentration in the perinuclear region (Fig. 1g, h).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe starvation-induced increase in TMEM55B mRNA is not observed in TFEB/TFE3 double knockout MEFs, indicating it is TFEB/TFE3-dependent.
“Starvation also significantly increased TMEM55B mRNA levels, and this increase was TFEB/TFE3-dependent since it was not observed in TFEB/TFE3 double knockout MEFs (Fig. 6f).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataRetrograde movement is detectable as early as 5 min following rapamycin induction, with near complete clustering of endosomes after 30 min.
“Transport was exceedingly rapid, with retrograde movement detectable as early as 5 min following rapamycin induction (Supplementary Movie 1), and near complete clustering of endosomes after 30 min (Fig. 3b).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataTMEM55B co-localizes with lysosomal marker LAMP-1 but not with early endosome marker HRS.
“we found that TMEM55B co-localized with the lysosomal marker LAMP-1 (Fig. 1b, top) but not with early endosome marker hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) (Fig. 1b, bottom).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIncubation with p38 inhibitors prevents curcumin-induced lysosomal clustering and JIP4 recruitment to lysosomes.
“Interestingly, lysosomal clustering and JIP4 recruitment to lysosomes was prevented by incubation with p38 inhibitors, but not JNK or Erk1/2 inhibitors (Fig. 8g, h), thus revealing a novel and unexpected role of p38 in retrograde organelle transport.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataFull-length TMEM55A and its N-terminal domain lack the ability to bind JIP4.
“full length TMEM55A, as well as its N-terminal domain (TMEM55A CD), lacked the ability to bind JIP4 (Fig. 4b).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataJIP4-depleted cells exhibit almost complete peripheral accumulation of lysosomes and late endosomes, with more than 60% of LAMP-1 signal in the distal region (>15 μm from nuclear rim).
“JIP4-depleted cells exhibited almost complete peripheral accumulation of both lysosomes (Fig. 5a) and late endosomes (Supplementary Fig. 5c), with more than 60% of the LAMP-1 signal falling in the distal region of the cell (>15 μm from the nuclear rim) (Fig. 5b).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataJNK or Erk1/2 inhibitors do not prevent curcumin-induced lysosomal clustering and JIP4 recruitment to lysosomes.
“Interestingly, lysosomal clustering and JIP4 recruitment to lysosomes was prevented by incubation with p38 inhibitors, but not JNK or Erk1/2 inhibitors (Fig. 8g, h), thus revealing a novel and unexpected role of p38 in retrograde organelle transport.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataTreatment of U2OS cells with NaAsO2 results in a clear shift in TMEM55B electrophoretic mobility and an increase in TMEM55B dimerization.
“Treatment of U2OS cells with NaAsO2 resulted in a clear shift in TMEM55B electrophoretic mobility, as well as an increase in TMEM55B dimerization (Fig. 8e), suggesting that TMEM55B might undergo post-translational modifications in response to acute stress.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataMutation of the Cx5R motif in TMEM55B full-length does not alter the ability of TMEM55B to induce lysosomal clustering or interact with JIP4.
“Mutation of the Cx5R motif in TMEM55B full-length did not alter the ability of this protein to induce lysosomal clustering or interact with JIP4 (Supplementary Fig. 8a, b).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataAlanine substitutions of Leucine10 and Leucine11 cause accumulation of full-length TMEM55B at the cell surface, with a minor fraction co-localizing with LAMP-1-positive structures.
“alanine substitutions of Leucine10 and Leucine11, residues of a putative acidic-dileucine motif at the amino termini of TMEM55B, caused accumulation of the full-length protein at the cell surface, with a minor fraction co-localizing with LAMP-1-positive structures (Supplementary Fig. 2b).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataGFP-TMEM55B CD exhibits a cytosolic distribution, whereas TMEM55B TM localizes predominantly to the plasma membrane.
“GFP-TMEM55B CD exhibited a cytosolic distribution, whereas TMEM55B TM localized predominantly to the plasma membrane.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataConstitutive active TFEB (S211A) and TFE3 (S321A) increase TMEM55B mRNA and protein levels in ARPE-19 cells.
“As expected, TFEB and TFE3 caused a significant increase in TMEM55B mRNA and protein levels (Fig. 6a–c), thus confirming that these transcription factors modulate TMEM55B expression.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataJIP4 displays no interaction with either RILP or ORP1L.
“JIP4 displayed no interaction with either RILP or ORP1L (Supplementary Fig. 6b)”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataFull-length GFP-TMEM55B and GFP-TMEM55B CD bind endogenous JIP4.
“we detected binding of both proteins to endogenous JIP4 (Fig. 4b).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationLysosome retrograde transport toward the immunological synapse is essential for natural killer and cytotoxic T lymphocyte killing of pathogen-infected cells.
“Lysosome retrograde transport toward the immunological synapse is essential for the ability of natural killer and cytotoxic T lymphocytes to kill pathogen infected cells15”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] Stinchcombe, J. C., Majorovits, E., Bossi, G., Fuller, S. & Griffiths, G. M. Centrosome polarization delivers secretory granules to the immunological synapse. Nature 443, 462–465 (2006). source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationAnterograde movement of lysosomes is regulated by BORC, Arl8, and SKIP, which links lysosomes to kinesin.
“Anterograde movement of lysosomes is regulated by the multi-subunit complex BORC, the small GTPase Arl8, and its effector SKIP, which directly interacts with the kinesin light chain, thus linking lysosomes to the plus-end-directed microtubule motor kinesin19,20.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [19] Rosa-Ferreira, C. & Munro, S. Ar18 and SKIP act together to link lysosomes to kinesin-1. Dev. Cell 21, 1171–1178 (2011). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [20] Pu, J. et al. BORC, a multisubunit complex that regulates lysosome positioning. Dev. Cell 33, 176–188 (2015). source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationTFEB and TFE3 promote expression of multiple lysosomal genes and are master regulators of lysosomal biogenesis.
“The transcription factors TFEB and TFE3 exhibit the unique ability to promote expression of multiple lysosomal genes and are considered master regulators of lysosomal biogenesis2,3.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [2] Sardiello, M. et al. A gene network regulating lysosomal biogenesis and function. Science 325, 473–477 (2009). source
- cites [3] Martina, J. A. et al. The nutrient-responsive transcription factor TFE3 promotes autophagy, lysosomal biogenesis, and clearance of cellular debris. Sci. Signal. 7, ra9 (2014). source
Probably not a substantial claim.
Study design and conductnone givenThirty or more cells were quantified per cell treatment and averaged to quantify the population lysosome distribution.
“Thirty or more cells were quantified per cell treatment and averaged to quantify the population lysosome distribution.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenNo portion of the cell was measured more than once.
“No portion of the cell was measured more than once.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataThe TMEM55B/JIP4/dynein-dynactin pathway regulates the constitutive bi-directional transport of lysosomes and also acts on-demand to promote retrograde lysosomal transport under certain stress conditions.
“In this regard, the TMEM55B/JIP4/dynein–dynactin pathway is particularly interesting, since it exhibits a dual function. It regulates the constitutive bi-directional transport of lysosomes but it also acts “on-demand” to promote retrograde lysosomal transport under certain stress conditions.”
Quote in the paperSubstantial claim- Rests on an assumption: Lysosomes undergo bidirectional transport along microtubules through the opposite activities of dynein and kinesins.
It may state two separate claims as one.
InterpretationreasoningIncreased TMEM55B levels favor movement of lysosomes toward the center of the cell, promoting fusion between lysosomes and autophagosomes to ensure efficient autophagic flux.
“Increased TMEM55B levels will favor movement of lysosomes toward the center of the cell, promoting fusion between lysosomes and autophagosomes to ensure efficient autophagic flux.”
Quote in the paperSubstantial claim- Rests on an assumption: Lysosome transport to the perinuclear region following starvation is critical to facilitate autophagosome–lysosome interactions and controls the rate of autophagosome degradation.
It may state two separate claims as one.
Interpretationown dataTMEM55B CD is both necessary and sufficient to drive retrograde trafficking of TMEM55B-targeted membranes, and does so by linking organelles to dynein motors.
“Based on these results, we concluded that TMEM55B CD is both necessary and sufficient to drive retrograde trafficking of TMEM55B-targeted membranes, and does so by linking organelles to dynein motors.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
InterpretationreasoningThe resulting increase in TMEM55B levels promotes transport of lysosomes to the perinuclear region and likely facilitates lysosome/ER interactions.
“The resulting increase in TMEM55B levels promoted transport of lysosomes to the perinuclear region and likely facilitated lysosome/ER interactions.”
Quote in the paperSubstantial claim- Rests on an assumption: Free cholesterol is transferred from lysosomes to other cellular compartments in a process that requires transport and tethering of late endosomes/lysosomes with ER membranes.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenAmplification of the sequence of interest was normalized with a reference endogenous gene Glyceraldehyde 3-phosphate dehydrogenase (GAPDH).
“Amplification of the sequence of interest was normalized with a reference endogenous gene Glyceraldehyde 3-phosphate dehydrogenase (GAPDH).”
Quote in the paperNot a substantial claimProbably not a substantial claim.
Study design and conductnone givenTwenty or more cells were quantified per cell treatment and averaged to quantify the population lysosome distribution.
“Twenty or more cells were quantified per cell treatment and averaged to quantify the population lysosome distribution.”
Quote in the paperSubstantial claimProbably not a substantial claim.
Study design and conductnone givenLine scans were drawn in various regions of the cell to accurately sample total LAMP-1 distribution.
“Line scans were drawn in various regions of the cell to accurately sample total LAMP-1 distribution.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
InterpretationreasoningInhibition of cholesterol efflux from lysosomes in U18666A-treated cells promotes activation of SREBF2 at the ER and TFEB/3 at the lysosomes.
“Inhibition of cholesterol efflux from lysosomes in U18666A-treated cells was sensed by different cellular compartments, promoting activation of SREBF2 at the ER and TFEB/3 at the lysosomes.”
Quote in the paperSubstantial claim- Rests on an assumption: LDL-bound cholesterol enters cells via endocytosis and is delivered to lysosomes to be converted into unesterified cholesterol.
- Rests on an assumption: Free cholesterol is transferred from lysosomes to other cellular compartments in a process that requires transport and tethering of late endosomes/lysosomes with ER membranes.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationALG-2 interacts with MCOLN1 in a calcium-dependent manner to recruit dynein-dynactin to lysosomes.
“ALG-2 interacts with the lysosomal transient receptor potential channel MCOLN1 in a calcium-dependent manner to recruit dynein–dynactin to lysosomes28,29.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [28] Li, X. et al. A molecular mechanism to regulate lysosome motility for lysosome positioning and tubulation. Nat. Cell Biol. 18, 404–417 (2016). source
- cites [29] Vergarajauregui, S., Martina, J. A. & Puertollano, R. Identification of the penta-EF-hand protein ALG-2 as a Ca2+-dependent interactor of mucolipin-1. J. Biol. Chem. 284, 36357–36366 (2009). source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
Interpretationown dataTMEM55B clusters lysosomes by recruiting the microtubule minus-end motor dynein to lysosomes, disrupting the balance of microtubule motors directing lysosomal trafficking.
“Thus, it was concluded that TMEM55B clusters lysosomes by recruiting the microtubule minus-end motor dynein to lysosomes, disrupting the balance of positive- and minus-end microtubule motors directing lysosomal trafficking.”
Quote in the paperSubstantial claim- Rests on an assumption: In non-polarized cells, microtubule minus-ends localize to the perinuclear region, close to the MTOC, whereas plus-ends are directed toward the cell periphery.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationA tripartite complex between Rab7, FYCO1, and kinesin promotes outward lysosomal movement.
“a tripartite complex between Rab7, FYCO1, and kinesin has also been shown to promote outward lysosomal movement21,22.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [21] Matsuzaki, F., Shirane, M., Matsumoto, M. & Nakayama, K. I. Protrudin serves as an adaptor molecule that connects KIF5 and its cargoes in vesicular transport during process formation. Mol. Biol. Cell 22, 4602–4620 (2011). source
Checked before — its earlier verdict is held back until a new check runs.
- cites [22] Raiborg, C., Wenzel, E. M., Pedersen, N. M. & Stenmark, H. ER-endosome contact sites in endosome positioning and protrusion outgrowth. Biochem. Soc. Trans. 44, 441–446 (2016). source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenWestern blots are representative of three or more independent experiments.
“Western blots are representative of three or more independent experiments.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataTMEM55B does not function as a bona fide PtdIns-4,5-P2 4-phosphatase, and its role in retrograde trafficking is independent of its Cx5R motif.
“Therefore, our results suggest that TMEM55B does not function as a bona fide PtdIns-4,5-P2 4-phosphatase and its role in retrograde trafficking is independent of its Cx5R motif.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenFor each measurement, blank measurements (20 μM substrate with no enzyme, as well as 250 ng protein with no substrate) were subtracted.
“For each measurement, blank measurements (20 µM substrate with no enzyme, as well as 250 ng protein with no substrate) were subtracted.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenCell images are representative from three or more independent experiments.
“Cell images are representative from three or more independent experiments.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
PremisecitationJIP4 is a scaffold protein that interacts with c-Jun NH2-terminal kinase (JNK) and functions as an activator of the p38 mitogen-activated protein (MAP) kinase pathway.
“JIP4 is a scaffold protein that interacts with c-Jun NH2-terminal kinase (JNK) and functions as an activator of the p38 mitogen-activated protein (MAP) kinase pathway56, suggesting that JIP4 might link transport of lysosomes to signaling.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [56] Kelkar, N., Standen, C. L. & Davis, R. J. Role of the JIP4 scaffold protein in the regulation of mitogen-activated protein kinase signaling pathways. Mol. Cell Biol. 25, 2733–2743 (2005). source
Probably not a substantial claim.
Study design and conductnone givenExperiments involving siRNA-induced knockdown of indicated proteins are representative of three or more independent experiments.
“Experiments involving siRNA-induced knockdown of indicated proteins are representative of three or more independent experiments.”
Quote in the paperSubstantial claimProbably not a substantial claim. The authors may not put it forward as true. The paper may give no reason why it holds.
InterpretationreasoningThe interaction of TMEM55B with the JIP4-dynactin complex helps bring dynein to the lysosomal surface, thus promoting retrograde transport.
“Here we postulate that the interaction of TMEM55B with the JIP4–dynactin complex helps bring dynein to the lysosomal surface, thus promoting retrograde transport.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataTMEM55B CD is required for targeting to lysosomes, and a significant fraction of TMEM55B traffics through the plasma membrane before reaching the endo-lysosomal compartment.
“Altogether, these results indicate that TMEM55B CD is required for targeting to lysosomes, and that a significant fraction of TMEM55B traffics through the plasma membrane before reaching the endo-lysosomal compartment.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataFull-length TMEM55B is required for proper localization to the endo-lysosomal compartment, and one or more endo/lysosomal targeting motifs likely reside within TMEM55B CD.
“These results suggest that the full-length protein is required for proper localization to the endo-lysosomal compartment and that one or more endo/lysosomal targeting motifs likely reside within TMEM55B CD.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Starvation activates TFEB and TFE3.
“TMEM55B levels are transcriptionally upregulated following TFEB and TFE3 activation by starvation or cholesterol-induced lysosomal stress.”
The paper relies on this without support.
Cholesterol accumulation in lysosomes activates TFEB and TFE3.
“TMEM55B levels are transcriptionally upregulated following TFEB and TFE3 activation by starvation or cholesterol-induced lysosomal stress.”
The paper relies on this without support.
In non-polarized cells, microtubule minus-ends localize to the perinuclear region, close to the MTOC, whereas plus-ends are directed toward the cell periphery.
“In non-polarized cells, microtubule minus-ends generally localize to the perinuclear region, close to the microtubule-organizing center (MTOC), whereas the microtubule plus-ends are directed toward the cell periphery.”
The paper relies on this without support.
JIP4 is a dynein adaptor/scaffold that links cargo to dynein–dynactin.
“we identified the dynein scaffold JIP4 as a major interacting protein of TMEM55B CD”
The paper relies on this without support.
Lysosome transport to the perinuclear region following starvation is critical to facilitate autophagosome–lysosome interactions and controls the rate of autophagosome degradation.
“Lysosome transport to the perinuclear region following starvation is critical to facilitate autophagosome–lysosome interactions and controls the rate of autophagosome degradation.”
The paper relies on this without support.
U18666A mimics the lack of functional Niemann-Pick type C protein responsible for NPC disease.
“It is well established that U18666A mimics the lack of functional Niemann-Pick type C protein responsible for the NPC disease.”
The paper relies on this without support.
In NPC1 and other lysosomal diseases, persistent accumulation of cholesterol in late endosomes/lysosomes leads to aberrant lysosomal clustering in the cell center.
“In NPC1 and other lysosomal diseases, the persistent accumulation of cholesterol in late endosomes/lysosomes leads to aberrant lysosomal clustering in the cell center.”
The paper relies on this without support.
Lysosomes undergo bidirectional transport along microtubules through the opposite activities of dynein and kinesins.
“Lysosomes undergo bidirectional transport along microtubules through the opposite activities of dynein and kinesins.”
The paper relies on this without support.
LDL-bound cholesterol enters cells via endocytosis and is delivered to lysosomes to be converted into unesterified cholesterol.
“LDL-bound cholesterol enters cells via endocytosis and it is delivered to lysosomes to be converted into unesterified cholesterol.”
The paper relies on this without support.
Free cholesterol is transferred from lysosomes to other cellular compartments in a process that requires transport and tethering of late endosomes/lysosomes with ER membranes.
“Free cholesterol is then transferred from lysosomes to other cellular compartments in a process that requires transport and tethering of late endosomes/lysosomes with the endoplasmic reticulum (ER) membranes.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
JIP4-mediated retrograde transport of lysosomes facilitates interaction and fusion between autophagosomes and lysosomes, resulting in degradation of autophagosomal content and restoration of energy homeostasis.
“JIP4-mediated retrograde transport of lysosomes facilitates interaction and fusion between autophagosomes and lysosomes, resulting in degradation of autophagosomal content and restoration of energy homeostasis7–9.”
From TMEM55B links autophagy flux, lysosomal repair, and TFE3 activation in response to oxidative stress (2024) · cites this paper as [7]
The Results section on starvation reports that JIP4 is required for lysosomes to cluster near the cell center and that JIP4 depletion impairs autophagosome–lysosome fusion and autophagic flux. The Introduction links this fusion to degradation of autophagosomal content. Our copy does not show that these effects restore energy homeostasis; it refers more generally to cellular homeostasis. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTMEM55B expression is dependent on TFEB.
“Interestingly, while TMEM55B expression is dependent on TFEB (Willett et al., 2017), TMEM55B can actually inhibit TFEB nuclear translocation (Hashimoto et al., 2018) thus suppressing expression of lysosomal genes.”
From Hippocampal TMEM55B overexpression in the 5XFAD mouse model of Alzheimer's disease (2024) · cites this paper as Willett et al., 2017
The Results section, “TFEB and TFE3 upregulate TMEM55B in response to starvation,” reports that TFEB increases TMEM55B mRNA and protein and that the starvation-induced increase is TFEB/TFE3-dependent. The claim omits both the starvation condition and TFE3’s role, making TFEB dependence sound more general than the evidence establishes. (LLM, conf=0.85)
Experimental — accuracy not yet measuredTMEM55B modulates lysosome function.
“TMEM55B is localized to the late endosome and lysosome7, and has been shown to impact lysosome function23, 28.”
From Phosphatidylinositol-(4,5)-Bisphosphate Regulates Plasma Cholesterol Through LDL (Low-Density Lipoprotein) Receptor Lysosomal Degradation (2020) · cites this paper as [28]
TMEM55B impacts lysosome function.
“TMEM55B is localized to the late endosome and lysosome7, and has been shown to impact lysosome function23, 28.”
From Phosphatidylinositol-(4,5)-Bisphosphate Regulates Plasma Cholesterol Through LDL (Low-Density Lipoprotein) Receptor Lysosomal Degradation (2020) · cites this paper as [28]
TMEM55B impacts lysosome positioning in AREP-19 and HeLa cells.
“very recently TMEM55B was reported to impact lysosome positioning in AREP-19 and HeLa cells28.”
From Phosphatidylinositol-(4,5)-Bisphosphate Regulates Plasma Cholesterol Through LDL (Low-Density Lipoprotein) Receptor Lysosomal Degradation (2020) · cites this paper as [28]
TMEM55B was first identified as a PI(4,5)P2 phosphatase by Ungewickell et al, but a recent study by Willett et al failed to detect PI(4,5)P2 hydrolysis activity of TMEM55B.
“Although TMEM55B was first identified as a PI(4,5)P2 phosphatase by Ungewickell et al7, a recent study by Willett et al failed to detect PI(4,5)P2 hydrolysis activity of TMEM55B28.”
From Phosphatidylinositol-(4,5)-Bisphosphate Regulates Plasma Cholesterol Through LDL (Low-Density Lipoprotein) Receptor Lysosomal Degradation (2020) · cites this paper as [28]
KD of TMEM55B drives microtubule-dependent transport of lysosomes to the cell's periphery.
“Overexpression of TMEM55B in ARPE19 or HeLa cells leads to perinuclear clustering of lysosomes, and KD drives microtubule-dependent transport of lysosomes to the cell's periphery.”
From TMEM55B promotes anterograde transport and distal axonal distribution of LAMP1-positive organelles (2026) · cites this paper as Willett et al., 2017
JIP4 binds dynein/dynactin and mediates retrograde lysosomal transport.
“JIP4 binds dynein/dynactin and mediates retrograde lysosomal transport (Willett et al., 2017).”
From TMEM55B promotes anterograde transport and distal axonal distribution of LAMP1-positive organelles (2026) · cites this paper as Willett et al., 2017
TMEM55B plays a critical role in the microtubule-dependent retrograde positioning of lysosomes upon overexpression and knockdown in non-neuronal cell-based models.
“TMEM55B plays a critical role in the microtubule-dependent retrograde positioning of lysosomes upon overexpression and knockdown (KD) in non-neuronal cell-based models (Willett et al., 2017).”
From TMEM55B promotes anterograde transport and distal axonal distribution of LAMP1-positive organelles (2026) · cites this paper as Willett et al., 2017
This phosphatase function was later challenged, and phosphatase activity could not be reproduced.
“This function was later challenged (Pal et al., 2023;Willett et al., 2017), and phosphatase activity could not be reproduced.”
From TMEM55B promotes anterograde transport and distal axonal distribution of LAMP1-positive organelles (2026) · cites this paper as Willett et al., 2017
TMEM55B recruits the cytosolic scaffold protein JIP4, which serves as a platform for both microtubule motor proteins dynein and kinesin-1.
“TMEM55B recruits the cytosolic scaffold protein JIP4 (Willett et al., 2017), which serves as a platform for both microtubule motor proteins dynein and kinesin-1.”
From TMEM55B promotes anterograde transport and distal axonal distribution of LAMP1-positive organelles (2026) · cites this paper as Willett et al., 2017
KD of JIP4 drives lysosomes into the cell's periphery.
“Likewise, the KD of JIP4 drives lysosomes into the cell's periphery (Willett et al., 2017).”
From TMEM55B promotes anterograde transport and distal axonal distribution of LAMP1-positive organelles (2026) · cites this paper as Willett et al., 2017
Overexpression of TMEM55B in ARPE19 or HeLa cells leads to perinuclear clustering of lysosomes.
“Overexpression of TMEM55B in ARPE19 or HeLa cells leads to perinuclear clustering of lysosomes, and KD drives microtubule-dependent transport of lysosomes to the cell's periphery.”
From TMEM55B promotes anterograde transport and distal axonal distribution of LAMP1-positive organelles (2026) · cites this paper as Willett et al., 2017
TMEM55A overexpression does not affect lysosomal positioning.
“TMEM55A overexpression does not affect lysosomal positioning (Willett et al., 2017), suggesting it may have functions independent of lysosomal positioning.”
From TMEM55B promotes anterograde transport and distal axonal distribution of LAMP1-positive organelles (2026) · cites this paper as Willett et al., 2017
Expression of recombinant TMEM55B induces lysosomal clustering in the perinuclear region.
“As we have previously described, expression of recombinant TMEM55B induced lysosomal clustering in the perinuclear region (Fig. 1g)7.”
From TMEM55B links autophagy flux, lysosomal repair, and TFE3 activation in response to oxidative stress (2024) · cites this paper as [7]
TMEM55B is an important regulator of lysosomal positioning.
“Our laboratory previously identified TMEM55B as an important regulator of lysosomal positioning.”
From TMEM55B links autophagy flux, lysosomal repair, and TFE3 activation in response to oxidative stress (2024) · cites this paper as [7]
TMEM55B over-expression causes lysosomes to collapse into the cell center, whereas depletion of either TMEM55B or JIP4 results in dispersion toward the cell periphery.
“TMEM55B over-expression causes lysosomes to collapse into the cell center, whereas depletion of either TMEM55B or JIP4 results in dispersion toward the cell periphery.”
From TMEM55B downregulation promotes neurodegeneration in Alzheimer’s disease models (2026) · cites this paper as Willett et al. 2017
TMEM55B interacts with JIP4.
“TMEM55B, an integral lysosomal membrane protein with two transmembrane segments, a large N-terminal cytoplasmic domain, and a short cytoplasmic C-terminus, interacts with JIP4.”
From TMEM55B promotes anterograde transport and distal axonal distribution of LAMP1-positive organelles (2026) · cites this paper as Willett et al., 2017
Activation of TFEB/TFE3 following starvation increases TMEM55B protein levels, leading to increased JIP4 recruitment to the lysosomal surface.
“Activation of TFEB/TFE3 following starvation increases TMEM55B protein levels, leading to increased JIP4 recruitment to the lysosomal surface7.”
From TMEM55B links autophagy flux, lysosomal repair, and TFE3 activation in response to oxidative stress (2024) · cites this paper as [7]
TMEM55B is a lysosomal transmembrane protein that binds to the dynein adapter JIP4, promoting dynein-dynactin-dependent lysosomal trafficking to the perinuclear region.
“TMEM55B is a lysosomal transmembrane protein that binds to the dynein adapter JIP4, thus promoting dynein-dynactin-dependent lysosomal trafficking to the perinuclear region7.”
From TMEM55B links autophagy flux, lysosomal repair, and TFE3 activation in response to oxidative stress (2024) · cites this paper as [7]
Treatment with NaAsO2 causes robust JIP4-dependent clustering of lysosomes at the cell center.
“Paradoxically, treatment with NaAsO2 causes robust JIP4-dependent clustering of lysosomes at the cell center7.”
From TMEM55B links autophagy flux, lysosomal repair, and TFE3 activation in response to oxidative stress (2024) · cites this paper as [7]
TMEM55B recruits the dynein adaptor JIP4 to lysosomes, promoting retrograde transport, while depletion of TMEM55B or JIP4 causes peripheral lysosome accumulation.
“It recruits the dynein adaptor JIP4 to lysosomes, promoting retrograde transport, while depletion of TMEM55B or JIP4 causes peripheral lysosome accumulation (Willett et al. 2017).”
From TMEM55B downregulation promotes neurodegeneration in Alzheimer’s disease models (2026) · cites this paper as Willett et al. 2017
Activation of TFEB and TFE3 results in a significant increase in TMEM55B mRNA and protein levels.
“Activation of TFEB and TFE3 resulted in a significant increase in TMEM55B mRNA and protein levels, supporting a role for these transcription factors in modulating TMEM55B expression (Willett et al. 2017) .”
From TMEM55B downregulation promotes neurodegeneration in Alzheimer’s disease models (2026) · cites this paper as Willett et al. 2017
TMEM55B promotes lysosomal retrograde transport.
“They showed that TMEM55B promotes lysosomal retrograde transport.”
From TMEM55B downregulation promotes neurodegeneration in Alzheimer’s disease models (2026) · cites this paper as Willett et al. 2017
Reduction of either TMEM55B or JIP4 caused a dramatic accumulation of lysosomes at the cell periphery without affecting the distribution of early endosomes or the Golgi apparatus.
“They also found that reduction of either TMEM55B or JIP4 caused a dramatic accumulation of lysosomes at the cell periphery without affecting the distribution of early endosomes or the Golgi apparatus.”
From TMEM55B downregulation promotes neurodegeneration in Alzheimer’s disease models (2026) · cites this paper as Willett et al. 2017
TMEM55B is a target of TFEB and TFE3, and TFEB and TFE3 modulate lysosomal positioning in response to nutrient deprivation and lysosomal stress by regulating TMEM55B expression levels.
“Since TMEM55B is a target of TFEB and TFE3, they proposed that, by regulating TMEM55B, expression levels [either by TFEB/3 activation by starvation or cholesterol accumulation in lysosomes]; TFEB and TFE3 modulate lysosomal positioning in response to nutrient deprivation and lysosomal stress.”
From TMEM55B downregulation promotes neurodegeneration in Alzheimer’s disease models (2026) · cites this paper as Willett et al. 2017
TMEM55B is a TFEB/TFE3 target induced by starvation and cholesterol stress.
“TMEM55B is a TFEB/TFE3 target induced by starvation and cholesterol stress (Willett et al. 2017).”
From TMEM55B downregulation promotes neurodegeneration in Alzheimer’s disease models (2026) · cites this paper as Willett et al. 2017
The lysosomal protein TMEM55B interacts and recruits the dynein adaptor JIP4 to lysosomal membranes, thus inducing retrograde transport of lysosomes along microtubules.
“They found that the lysosomal protein TMEM55B interacts and recruits the dynein adaptor JIP4 to lysosomal membranes, thus inducing retrograde transport of lysosomes along microtubules.”
From TMEM55B downregulation promotes neurodegeneration in Alzheimer’s disease models (2026) · cites this paper as Willett et al. 2017
Puertollano and coworkers showed TMEM55B recruits JIP4 to lysosomes, promoting dynein-dependent retrograde transport, and depletion causes peripheral lysosome accumulation without affecting endosomes or Golgi.
“Puertollano and coworkers (Willett et al. 2017) showed TMEM55B recruits JIP4 to lysosomes, promoting dynein-dependent retrograde transport, and depletion causes peripheral lysosome accumulation without affecting endosomes or Golgi.”
From TMEM55B downregulation promotes neurodegeneration in Alzheimer’s disease models (2026) · cites this paper as Willett et al. 2017
TMEM55B transcription is regulated by the lysosomal regulator TFEB, which is dysregulated in Alzheimer's disease.
“TMEM55B transcription is regulated by the master autophagic and lysosomal regulator TFEB (Willett et al., 2017) which is dysregulated in AD (Zhang & Zhao, 2015).”
From Hippocampal TMEM55B overexpression in the 5XFAD mouse model of Alzheimer's disease (2024) · cites this paper as Willett et al., 2017
TMEM55B (PIP4P1) is a key player in the retrograde trafficking of lysosomes in multiple cell types.
“Transmembrane protein 55B (TMEM55B), also known as phosphatidylinositol-4,5bisphosphate 4-phosphatase 1 (PIP4P1), is a key player in the retrograde trafficking of lysosomes in multiple cell types (Araki & Kontani, 2021;Rudnik et al., 2022;Takemasu et al., 2019;Willett et al., 2017).”
From Hippocampal TMEM55B overexpression in the 5XFAD mouse model of Alzheimer's disease (2024) · cites this paper as Willett et al., 2017
TMEM55B regulates lysosome positioning and trafficking via interaction with the JIP4 motor protein adapter.
“TMEM55B regulates lysosome positioning and trafficking via interaction with the JIP4 motor protein adapter (Willett et al., 2017) independently from its phosphatase function (Takemasu et al., 2019) but dependent on S-palmitoylation (Rudnik et al., 2022).”
From Hippocampal TMEM55B overexpression in the 5XFAD mouse model of Alzheimer's disease (2024) · cites this paper as Willett et al., 2017
TMEM55B activity may mitigate amyloid β plaque-associated lysosomal dysregulation, perhaps by promoting retrograde trafficking.
“This suggest that TMEM55B activity may mitigate Aβ plaque-associated lysosomal dysregulation perhaps by promoting retrograde trafficking (Willett et al., 2017).”
From Hippocampal TMEM55B overexpression in the 5XFAD mouse model of Alzheimer's disease (2024) · cites this paper as Willett et al., 2017
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
NaAsO2 concentration differs for the U2OS experiment
MajorThe Fig. 8e caption specifies 150 μM NaAsO2 for U2OS cells, while the Methods specify 300 μM for acute oxidative stress in U2OS cells.
“e Immunoblot of U2OS expressing GFP-TMEM55B cells untreated or treated with 150 µM NaAsO2.”
“For acute oxidative stress in U2OS, cells were treated with 40 µM curcumin for 6 h, or 300 µM NaAsO2 for 2 h.”
Cell line differs for the TFEB/TFE3 expression experiment
MinorThe Results describe the experiment as using HeLa cells, while the caption for Fig. 6a-c identifies ARPE-19 cells.
“To confirm this, HeLa cells were infected with adenovirus expressing constitutive active versions of TFEB (Ad-TFEB-S211A) and TFE3 (Ad-TFE3-S321A)3,45.”
“a–c ARPE-19 cells were infected with adenovirus expressing TFE3-S321A-Myc, TFEB-S211A-FLAG, or null virus for 36 h.”
Fig. 7d gives a different treatment from the Results
MinorThe Results attribute the Fig. 7c,d response to U18666A, but the caption says the MEFs in Fig. 7d were starved in EBSS. These are different experimental treatments for a result used to support the cholesterol-response conclusion.
“Interestingly, U18666A induced TFE3 activation and TFEB/TFE3-dependent TMEM55B upregulation in MEFs, suggesting that the TFEB/TMEM55B/JIP4 pathway may also participate in the adaptation of lysosomal function and distribution in response to cholesterol (Fig. 7c, d).”
“d Relative quantitative real-time PCR analysis of TMEM55B mRNA transcript levels from null- or TFE3/TFEB knockout MEFs, untreated or starved in EBSS for 4 h”
Fig. 7e gives a different treatment from the Results
MinorThe Results identify Fig. 7e as evidence about U18666A-mediated lysosomal clustering, whereas its caption says the cells were starved in EBSS. The caption therefore does not describe the treatment underlying the stated conclusion.
“Accordingly, depletion of TMEM55B, or more dramatically JIP4, prevented U18666A-mediated lysosomal clustering without affecting U18666A-induced lysosomal enlargement (Fig. 7e and Supplementary Fig. 9e).”
“e HeLa cells depleted of TMEM55B, JIP4, or control RNAi were starved in EBSS for 4 h and then immunostained with antibody against LAMP-1.”
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Metadata
- Authors
- Willett, R., Martina, J. A., Zewe, J. P., Wills, R., Hammond, G. R. V., & Puertollano, R.
- Affiliations
- National Institutes of Health (US)
- University of Pittsburgh (US)
- Corresponding author
- Puertollano, Rosa
- Venue
- Nature Communications
- Published
- 2017-11-17
- Volume
- 8
- Issue
- 1
- Pages
- 1580-1580
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5691037
- OpenAlex
- W2770609313
- Cited by
- 201
- References
- 65
- Citations by year
- 2026: 15 · 2025: 31 · 2024: 27 · 2023: 25 · 2022: 28 · 2021: 29 · 2020: 27 · 2019: 10 · 2018: 8
- FWCI
- 4.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Institute of General Medical Sciences (R35GM119412)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- TFEB, JIP4, autophagosome-lysosome fusion, lysosomal trafficking, starvation, lysosomal storage disease, microtubules
- MeSH terms
- Phosphoinositide Phosphatases, Animals, Chlorocebus aethiops, Gene Expression Regulation, HeLa Cells, Humans, Lysosomes, Microtubules, COS Cells, Protein Transport, Vesicular Transport Proteins, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Lysosomal Membrane Proteins
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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