Noncanonical autophagy promotes the visual cycle
Open accessAbstract
SUMMARY Phagocytosis and degradation of photoreceptor outer segments (POS) by the retinal pigment epithelium (RPE) is fundamental to vision. Autophagy is also responsible for bulk degradation of cellular components but its role in POS degradation is not well understood. We report that the morning burst of RPE phagocytosis coincided with the enzymatic conversion of autophagy protein LC3 to its lipidated form. LC3 then associated with single membrane phagosomes containing engulfed POS in an Atg5 dependent manner that required Beclin1 but not the autophagy pre-initiation complex. The importance of this process was verified in mice with Atg5-deficient RPE cells that showed evidence of disrupted lysosomal processing. These mice also exhibited decreased photoreceptor responses to light stimuli and decreased chromophore levels that were restored with exogenous retinoid supplementation. These results establish that the interplay of phagocytosis and autophagy within the RPE are required for both POS degradation and the maintenance of retinoid levels to support vision.
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Written from the paper’s full text.
TL;DR
In the retinal pigment epithelium (RPE), phagocytosed photoreceptor outer segments (POS) recruit LC3 through a noncanonical autophagy pathway (LAP) that requires Atg5 and Beclin1 but not the autophagy pre-initiation complex. Atg5-deficient RPE mice show disrupted POS processing, reduced chromophore levels, and decreased visual function that is rescued by exogenous 9-cis retinal.
Key findings
- RPE LC3 lipidation is cyclical: LC3-II was most abundant in RPE at 7:00 AM (1 h after lights on) and much less at 7:00 PM; Atg5ΔRPE mice lost detectable LC3-II and GFP-LC3 punctae.
- LC3 associated with single-membrane phagosomes containing engulfed POS in an Atg5- and Beclin1-dependent manner, but silencing Fip200, Ulk1, or Atg13 did not prevent POS-induced LC3 association or LC3-II formation.
- Atg5ΔRPE mice at 16 weeks had significantly decreased rod and cone ERG responses to brighter light stimuli, without significant outer nuclear layer nuclei loss by 24 weeks or up to 1.5 years and without significant cone photoreceptor reduction.
- At 20 weeks, Atg5ΔRPE mice had significantly reduced 11-cis, all-trans, and 13-cis RAL compared with littermate controls, while all-trans retinyl-esters were not significantly different; intraperitoneal 9-cis RAL (0.25 mg/animal) restored rod and cone function after 24 h dark adaptation.
Methods
- Conditional Atg5 deletion in RPE was generated by crossing BEST1(VMD2)-cre mice with Atg5flox/flox mice; Ulk1−/− and Ulk1+/− mice were also used, with littermate controls.
- Rat RPE-J cells were differentiated with retinoic acid, fed bovine POS, and analyzed by confocal microscopy, time-lapse imaging, TEM, siRNA knockdowns, and phagocytosis assays.
- Retinoid analysis pooled 2 eyecups from 20-week Atg5ΔRPE (n=4) and Atg5f/f (n=5) mice; ERG and other experiments used at least 3 mice per group and were repeated at least 3 times; statistics used two-tailed unpaired Student’s t test with P<0.05 and standard error bars.
Limitations
- The paper states that the exact relationship between Atg5 function and the visual cycle is not completely understood and that further studies are required to uncover all molecular details of the coupling between phagocytosis and the visual cycle.
- Evident from the text: the conclusions rely on mouse RPE-specific Atg5 deletion and the rat RPE-J cell line, with no human data; the mechanism by which LAP supports retinoid recovery and chromophore synthesis is not fully resolved.
- Evident from the text: despite significant ERG deficits, no significant photoreceptor loss was detected, so the functional defect appears subtle and may involve processes beyond photoreceptor survival.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 42 cited sources checked · 0 supported · 0 flagged
- Findingown data
Chloroquine treatment does not cause accumulation of LC3-II in Atg5ΔRPE RPE.
“Upon treatment with chloroquine to block autophagic flux (Klionsky et al., 2012), RPE still failed to accumulate LC3-II in Atg5ΔRPE mice (Figure 1C) verifying the loss of Atg5.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Klionsky et al., 2012 source
Not checked in the free run.
- Findingown data
At 12 weeks, ERG responses in Atg5ΔRPE mice are indistinguishable from littermate controls.
“At 12 weeks ERG responses in the Atg5ΔRPE mice were indistinguishable from littermate control animals (Figure 2A); however, at 16 weeks Atg5ΔRPE mice exhibited significantly decreased rod response to brighter light stimuli compared to their littermate controls (Figure 2B).”
Quote in the paperNot a substantial claim - Findingown data
Atg5ΔRPE mice have decreased chromophore levels.
“These mice also exhibited decreased photoreceptor responses to light stimuli and decreased chromophore levels that were restored with exogenous retinoid supplementation.”
- Also stated in: § Non-canonical autophagy in the RPE contributes to the retinoid supply for the photoreceptors · plain
“the amounts of 11-cis, all-trans, and 13-cis RAL were significantly reduced in Atg5ΔRPE mice compared to littermate controls (Figure 7C).”
Quote in the paperSubstantial claim - Also stated in: § Non-canonical autophagy in the RPE contributes to the retinoid supply for the photoreceptors · plain
- Findingown data
The appearance of LC3-II in the RPE of adult mice is strikingly diminished in Atg5ΔRPE mice at 16 weeks.
“Further, the appearance of LC3-II in the RPE of adult mice was strikingly diminished in Atg5ΔRPE mice at this time (Figure 1B).”
Quote in the paperSubstantial claim - Findingown data
Atg5ΔRPE mice exhibit decreased photoreceptor responses to light stimuli.
“These mice also exhibited decreased photoreceptor responses to light stimuli and decreased chromophore levels that were restored with exogenous retinoid supplementation.”
- Also stated in: § Retinal function decreases in Atg5ΔRPE mice · plain
“at 16 weeks Atg5ΔRPE mice exhibited significantly decreased rod response to brighter light stimuli compared to their littermate controls (Figure 2B).”
- Also stated in: § Retinal function decreases in Atg5ΔRPE mice · plain
“cone responses from Atg5ΔRPE mice also showed comparable decreases to bright light stimuli compared to control mice (Figure 2B).”
Quote in the paperSubstantial claim - Also stated in: § Retinal function decreases in Atg5ΔRPE mice · plain
- Findingown data
In Atg5ΔRPE mice, phagosomes containing poorly processed POS accumulate.
“Examining POS in the RPE of Atg5ΔRPE mice revealed the accumulation of phagosomes that contain poorly processed POS (Figure 3E–G, arrowheads) suggesting disrupted lysosomal processing in the absence of Atg5.”
Quote in the paperSubstantial claim - Findingown data
At 16 weeks, Atg5ΔRPE mice exhibit significantly decreased rod response to brighter light stimuli compared to littermate controls.
“at 16 weeks Atg5ΔRPE mice exhibited significantly decreased rod response to brighter light stimuli compared to their littermate controls (Figure 2B).”
Quote in the paperSubstantial claim - Findingown data
Mice with Atg5-deficient RPE cells show evidence of disrupted lysosomal processing.
“The importance of this process was verified in mice with Atg5-deficient RPE cells that showed evidence of disrupted lysosomal processing.”
- Also stated in: § Atg5 and LC3 associate with single-membrane phagosomes containing POS · hedged
“Examining POS in the RPE of Atg5ΔRPE mice revealed the accumulation of phagosomes that contain poorly processed POS (Figure 3E–G, arrowheads) suggesting disrupted lysosomal processing in the absence of Atg5.”
Quote in the paperSubstantial claim - Also stated in: § Atg5 and LC3 associate with single-membrane phagosomes containing POS · hedged
- Findingown data
Without Atg5, POS do not penetrate much beyond the apical surface of the RPE at the examined time point.
“It was also notable that without Atg5, POS did not penetrate much beyond the apical surface of the RPE at this time point (Figure 3B, inset).”
Quote in the paperSubstantial claim - Findingown data
At 8 weeks, the LC3-II form is undetectable in control or Atg5ΔRPE RPE.
“The low level of Atg5 at 8 weeks was reflected in our inability to detect the LC3-II form in control or Atg5ΔRPE RPE suggesting that at this early age this pathway may not be functioning maximally.”
Quote in the paperNot a substantial claim - Findingown data
The morning burst of RPE phagocytosis coincides with the enzymatic conversion of autophagy protein LC3 to its lipidated form.
“We report that the morning burst of RPE phagocytosis coincided with the enzymatic conversion of autophagy protein LC3 to its lipidated form.”
- Also stated in: § Activity of the autophagy pathway is cyclically engaged in the RPE · plain
“we noted that this product of the autophagy pathway was most abundant in RPE at 7:00 AM (1 h after lights on) but much less LC3-II was observed when western blots were performed on RPE harvested at 7:00 PM (1 h into the dark cycle).”
Quote in the paperSubstantial claim - Also stated in: § Activity of the autophagy pathway is cyclically engaged in the RPE · plain
- Findingown data
LC3-II is readily detected in the retinas of adult mice throughout the day.
“While LC3-II was readily detected in the retinas of adult mice throughout the day, we noted that this product of the autophagy pathway was most abundant in RPE at 7:00 AM (1 h after lights on) but much less LC3-II was observed when western blots were performed on RPE harvested at 7:00 PM (1 h into the dark cycle).”
Quote in the paperNot a substantial claim - Findingown data
Atg5 does not associate with POS in Atg5ΔRPE RPE cells.
“Atg5 did not associate with the POS in Atg5ΔRPE RPE cells (Figure 3B).”
Quote in the paperSubstantial claim - Findingown data
At 16 weeks, cone responses from Atg5ΔRPE mice show comparable decreases to bright light stimuli compared to controls.
“Furthermore, cone responses from Atg5ΔRPE mice also showed comparable decreases to bright light stimuli compared to control mice (Figure 2B).”
Quote in the paperNot a substantial claim - Findingown data
At 8 weeks, Atg5 expression is detectable but less abundant in Atg5ΔRPE mice compared to littermate controls.
“At 8 weeks Atg5 expression was detectable (albeit less so) in the Atg5ΔRPE mouse compared to littermate control mice (Figure 1B).”
Quote in the paperNot a substantial claim - Findingown data
Atg5 co-localizes with LC3 in GFP-LC3 transgenic mice.
“as well as with LC3 in the GFP-LC3 transgenic mice (Figure 3C, arrows).”
Quote in the paperSubstantial claim - Findingown data
Atg5 co-localizes with engulfed POS in control mice.
“Strikingly, we found that Atg5 co-localized with engulfed POS in control mice (Figure 3A, arrows merged image) (visualized by rhodopsin staining (Nandrot et al., 2007)) as well as with LC3 in the GFP-LC3 transgenic mice (Figure 3C, arrows).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Nandrot et al., 2007 source
Not checked in the free run.
- Findingown data
No significant loss of nuclei in the outer nuclear layer is observed in Atg5ΔRPE mice by 24 weeks or up to 1.5 years.
“Although we observed a significant reduction in ERG responses we did not observe significant loss of nuclei in the outer nuclear layer (ONL) by 24 weeks (Figure 2C) or at any time examined up to 1.5 yrs. (not shown).”
Quote in the paperSubstantial claim - Findingown data
No significant reduction in cone photoreceptors is observed following PNA staining at any time point in Atg5ΔRPE mice.
“We also did not observe a significant reduction in cone photoreceptors when they were enumerated following PNA staining at any time point (Figure 2D, and data not shown).”
Quote in the paperSubstantial claim - Findingown data
Secondary effects on the expression of receptors involved in POS binding and phagocytosis due to the deletion of Atg5 were not observed in Atg5ΔRPE RPE cells compared to control.
“Secondary effects on the expression of receptors involved in POS binding and phagocytosis (Gal et al., 2000; Nandrot et al., 2007; Nandrot et al., 2004) due to the deletion of Atg5 were not observed in Atg5ΔRPE RPE cells compared to control (Figure S1).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Findingown data
Post-treatment with 9-cis RAL, there is no significant difference in rod and cone function between Atg5ΔRPE and control mice.
“While pre-treatment results confirmed the difference between Atg5ΔRPE and control, post-treatment results indicated no significant difference in rod and cone function between the two groups (Figure 7B).”
Quote in the paperSubstantial claim- Rests on an assumption: 9-cis RAL is a functional analog of the visual chromophore 11-cis RAL.
- Findingown data
Association of Atg5 with engulfed POS in RPE from Ulk1−/− mice is indistinguishable from that in Ulk1+− control animals.
“the association of Atg5 with engulfed POS in RPE from Ulk1−/− mice was indistinguishable from that in the RPE of Ulk1+− control animals (Fig 6C).”
Quote in the paperSubstantial claim - Findingown data
Upon engulfment of POS by RPE-J cells, LC3 associates with the POS.
“Upon engulfment, we noted association of LC3 with the POS (Figure 4A–E, lower left panels, arrows) and that this was dependent on several autophagy proteins as determined by silencing components of the conventional autophagy pathway.”
Quote in the paperSubstantial claim - Findingown data
Accumulation of LAMP1 and maturation of cathepsin D induced by POS exposure are diminished in RPE-J cells lacking Atg5.
“Further, the accumulation of LAMP1 and the maturation of cathepsin D, both induced by exposure of RPE-J cells to POS, were diminished in cells lacking Atg5 (Figure 5C) (single channel fluorescent images are provided in Figure S3A).”
Quote in the paperSubstantial claim - Findingown data
In RPE-J cells, engulfed POS co-localize with LAMP1, LAMP2, and cathepsin D, indicating that POS degradation proceeds.
“Indeed, we observed that in RPE-J cells engulfed POS co-localized with LAMP1, LAMP2, and cathepsin D (Figure 5A, left panels, arrows) indicating that POS degradation was proceeding (Bosch et al., 1993; Rakoczy et al., 1997; Ramkumar et al., 2010).”
Quote in the paperSubstantial claim0 of 3 sources checked - Findingcitation
A single treatment with 9-cis RAL provides only short-term functional rescue.
“This single treatment provided only short-term functional rescue as previously shown (Tang et al., 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Tang et al., 2010 source
Not checked in the free run.
- Findingown data
Silencing Atg5 or Beclin1 prevents POS-induced LAP in RPE-J cells.
“we found that the silencing of Atg5 (Figure 4A, lower right panel) or Beclin1 (Figure 4B, lower right) prevented POS-induced LAP as assessed visually (Figure 4A–B), or by LC3 conversion (Figure S2B).”
Quote in the paperSubstantial claim - Findingown data
Silencing of Atg5, Beclin1, Fip200, Ulk1, or Atg13 has little effect on the extent of uptake of POS.
“Silencing of any of these components had little effect on the extent of uptake of POS (Figure S2C), and all knockdowns disrupted conventional autophagy as assessed by rapamycin-induced GFP-LC3 punctae formation (Figure 4A–E, upper right panels) and accumulation of rapamycin-induced LC3-II (Figure S2C).”
Quote in the paperSubstantial claim - Findingown data
Silencing Atg5 prevents co-localization of LAMP1, LAMP2, and cathepsin D with engulfed POS in RPE-J cells.
“Silencing of Atg5 prevented co-localization of these molecules involved in phagosome maturation and cargo degradation (Figure 5B, arrows).”
Quote in the paperSubstantial claim - Findingown data
In Ulk1−/− mice in the morning, LC3-II is detected in RPE.
“When we examined RPE cells from Ulk1−/− mice in the morning (8:00 AM) when phagocytosis is maximal we detected LC3-II (Figure 6A); however, we also observed the accumulation of p62/SQSTM [a hallmark of defective autophagy (Klionsky et al., 2012; Mizushima et al., 2010; Takamura et al., 2011)] in the Ulk1−/− RPE indicating that the enzymatic production of LC3-II was likely due to POS induced LAP as”
Quote in the paperSubstantial claim - Findingown data
Significant quantities of ROL (any isomeric form) were not detected.
“Significant quantities of ROL (any isomeric form) were not detected.”
Quote in the paperNot a substantial claim - Findingown data
Unlike Atg5ΔRPE mice, ERG responses in Ulk1−/− animals show no defects.
“Further, unlike Atg5ΔRPE mice (Figure 2), the ERG responses in Ulk1−/− animals showed no defects (Figure 6B) and the association of Atg5 with engulfed POS in RPE from Ulk1−/− mice was indistinguishable from that in the RPE of Ulk1+− control animals (Fig 6C).”
Quote in the paperSubstantial claim - Findingown data
As POS are engulfed by RPE-J cells, they rapidly move through the epithelial layer past the nucleus toward the basal surface.
“As POS were engulfed by RPE-J cells, we noted that they rapidly moved through the epithelial layer past the nucleus (Figure 5D, dotted ovals) toward the basal surface of the cell (Figure 5D, left, dotted line).”
Quote in the paperSubstantial claim - Findingown data
Amounts of 11-cis, all-trans, and 13-cis RAL are significantly reduced in Atg5ΔRPE mice compared to littermate controls.
“The results, quantitated according to previously published protocol (Tang et al., 2011), show that the amounts of 11-cis, all-trans, and 13-cis RAL were significantly reduced in Atg5ΔRPE mice compared to littermate controls (Figure 7C).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Tang et al., 2011 source
Not checked in the free run.
- Findingown data
Atg5ΔRPE RPE cells have increased p62/SQSTM1.
“Autophagy- and LAP- defective Atg5ΔRPE RPE cells also had increased p62/SQSTM1 as expected.”
Quote in the paperNot a substantial claim - Findingown data
TEM analysis of RPE-J cells that had phagocytosed POS revealed only single membrane phagosomes.
“TEM analysis of RPE-J cells that had phagocytosed POS revealed only single membrane phagosomes (Figure 4F, black arrows).”
Quote in the paperSubstantial claim - Findingown data
No difference is found between control and Atg5ΔRPE RPE cells in quantities of RPE proteins involved in the visual cycle.
“Initially we examined the quantities of RPE proteins known to be involved in this multi-step enzymatic pathway and found no difference between control and Atg5ΔRPE RPE cells (Figure S4) suggesting that the machinery for intrinsic chromophore synthesis was in place.”
Quote in the paperSubstantial claim - Findingown data
Disruption of LAP in the RPE reduces ERG responses.
“Although we did not observe obvious decreases in rod and cone photoreceptor numbers, disruption of LAP in the RPE reduced ERG responses (see Figure 2).”
Quote in the paperSubstantial claim - Findingown data
The POS phagocytosis and degradation pathway is dependent on the autophagy proteins LC3, Atg5, and Beclin1.
“that is dependent on the autophagy proteins LC3, Atg5 and Beclin1”
Quote in the paperSubstantial claim - Findingown data
There are no significant changes in the levels of key visual cycle markers LRAT, RPE65, and CRALBP in Atg5-deficient RPE.
“We did not detect significant changes in the levels of these key visual cycle markers”
Quote in the paperSubstantial claim - Findingown data
The photoreceptor cell count in Atg5-deficient animals does not significantly differ from that of normal mice.
“the photoreceptor cell count in the Atg5-deficient animals did not significantly differ from that of normal mice”
Quote in the paperSubstantial claim - Findingcitation
In normal RPE cells, POS are contained in single membrane phagosomes.
“In normal RPE cells POS were contained in single membrane phagosomes as reported (Bosch et al., 1993; Gordiyenko et al., 2010; Strauss, 2005).”
Quote in the paperSubstantial claim0 of 3 sources checked - Findingown data
The loss of visual function in Atg5ΔRPE mice is restored by exogenous supplementation with the chromophore analog 9-cis RAL.
“the loss of visual function was restored by exogenous supplementation with the chromophore analog, 9-cis RAL.”
Quote in the paperSubstantial claim- Rests on an assumption: 9-cis RAL can substitute for 11-cis RAL to restore visual function in Atg5-deficient RPE.
- Findingown data
The Atg5-deficient RPE is unable to support optimal visual function, as evidenced by a consistent loss of ERG amplitudes with age.
“the Atg5-deficient RPE was unable to support optimal visual function as evidenced by a consistent loss of ERG amplitudes with age.”
Quote in the paperSubstantial claim - Findingown data
Uptake of POS is not impaired without Atg5.
“uptake of POS was not impaired without Atg5”
Quote in the paperSubstantial claim - Findingown data
Atg5ΔRPE mice have decreased 11-cis RAL compared to normal mice.
“Atg5ΔRPE mice had decreased 11-cis RAL compared to normal mice”
Quote in the paperSubstantial claim - Findingown data
Disruption of this non-canonical autophagy prevents POS degradation.
“and that its disruption not only prevented POS degradation”
Quote in the paperSubstantial claim - Findingown data
Degradation of outer segment tips following RPE phagocytosis is dependent on a non-canonical form of autophagy.
“Herein we show that degradation of outer segment tips following RPE phagocytosis is also dependent on a non-canonical form of autophagy”
Quote in the paperSubstantial claim - Findingown data
There is no difference in the levels of known phagocytic receptors on the RPE without Atg5.
“there was no difference in the levels of known phagocytic receptors on the RPE”
Quote in the paperSubstantial claim - Findingown data
In the absence of Atg5, degenerating phagosomes containing undigested POS material are prevalent.
“In the absence of Atg5 degenerating phagosomes containing undigested POS material were prevalent.”
Quote in the paperSubstantial claim - Findingown data
The POS phagocytosis and degradation pathway is not dependent on the autophagy pre-initiation complex composed of ULK1, FIP200, and ATG13.
“but not on the autophagy pre-initiation complex composed of ULK1, FIP200, and ATG13”
Quote in the paperSubstantial claim - Findingown data
Without Atg5, POS are unable to penetrate into the RPE in the same manner as in control cells.
“In addition, without Atg5 POS were unable to penetrate into the RPE in the same manner as in control cells.”
Quote in the paperSubstantial claim - Findingown data
Disruption of this non-canonical autophagy has a significant impact on vision.
“but had a significant impact on vision.”
Quote in the paperSubstantial claim - Findingown data
Lysosomal proteins Lamp1 and Lamp2 and the degradative enzyme cathepsin D are not able to associate with phagocytosed POS without Atg5.
“This was confirmed by our findings that the lysosomal proteins Lamp1 and Lamp2 and the degradative enzyme cathepsin D were not able to associate with the phagocytosed POS without Atg5.”
Quote in the paperSubstantial claim - Interpretationown data
The interplay of phagocytosis and autophagy within the RPE is required for both POS degradation and the maintenance of retinoid levels to support vision.
“These results establish that the interplay of phagocytosis and autophagy within the RPE are required for both POS degradation and the maintenance of retinoid levels to support vision.”
- Also stated in: § DISCUSSION · boosted
“Thus, we have established a link between RPE phagocytosis, autophagy, and the visual cycle.”
Quote in the paperSubstantial claim- Rests on an assumption: The RPE takes up 11-cis RAL bound to opsin and probably other forms of retinoids from the photoreceptors through daily phagocytosis.
- Also stated in: § DISCUSSION · boosted
- Interpretationown data
The absence of abundant double-membrane autophagosomes containing outer segments suggests an alternative to a role for conventional autophagy in POS uptake and degradation.
“This, together with the absence of abundant double-membrane autophagosomes containing outer segments suggested an interesting alternative to a role for conventional autophagy in the process of POS uptake and degradation.”
Quote in the paperSubstantial claim - Interpretationown data
Under basal conditions RPE cells have significant levels of LC3-II conversion that is linked to the time of day.
“Thus, under basal conditions RPE cells have significant levels of LC3-II conversion that is linked to the time of day.”
Quote in the paperSubstantial claim - Interpretationown data
LAP may be linked to other functions of RPE cells that support visual function.
“This suggests that LAP may be linked to other functions of the RPE cells that support visual function.”
Quote in the paperNot a substantial claim - Interpretationown data
The deficit in visual function in Atg5ΔRPE mice can be attributed to an inadequate recovery of retinoids due to disruption of the non-canonical pathway of autophagy.
“These results are consistent with the idea that the deficit in visual function in Atg5ΔRPE mice can be attributed to an inadequate recovery of retinoids due to disruption of the non-canonical pathway of autophagy.”
Quote in the paperSubstantial claim- Rests on an assumption: The RPE takes up 11-cis RAL bound to opsin and probably other forms of retinoids from the photoreceptors through daily phagocytosis.
- Interpretationown data
Non-canonical autophagy supports optimal visual function by supplying a portion of the retinoids required for chromophore synthesis.
“Importantly, our studies show that this non-canonical form of autophagy supported optimal visual function by supplying a portion of the retinoids required for chromophore synthesis.”
Quote in the paperSubstantial claim- Rests on an assumption: The RPE takes up 11-cis RAL bound to opsin and probably other forms of retinoids from the photoreceptors through daily phagocytosis.
- Premisecitation
There is a functional convergence of autophagy and phagocytosis where components of the autophagy pathway are co-opted by phagocytosis to increase degradation of phagocytosed cargo by aiding lysosome/phagosome fusion and phagolysosome maturation.
“Recent studies from several laboratories (DeSelm et al., 2011; Florey et al., 2011; Henault et al., 2012; Martinez et al., 2011) have shown that there is a functional convergence of autophagy and phagocytosis where components of the autophagy pathway have been co-opted by phagocytosis to increase the efficient degradation of the phagocytosed cargo by aiding in lysosome/phagosome fusion as well as”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
The phagocytic function of the RPE and the visual cycle are linked via a non-canonical form of autophagy.
“Studies presented here show that the phagocytic function of the RPE and the visual cycle are linked via a non-canonical form of autophagy.”
Quote in the paperSubstantial claim- Rests on an assumption: The RPE takes up 11-cis RAL bound to opsin and probably other forms of retinoids from the photoreceptors through daily phagocytosis.
- Interpretationreasoning
A link between RPE phagocytosis, autophagy, and the visual cycle is established.
“Thus, we have established a link between RPE phagocytosis, autophagy, and the visual cycle.”
Quote in the paperSubstantial claim - Interpretationown data
LAP is necessary for the degradation of phagocytosed outer segments.
“This process, termed LAP, was necessary for the degradation of the phagocytosed outer segments.”
Quote in the paperSubstantial claim - Interpretationown data
Phagosomes require Atg5 to move through the RPE and enter the lysosomal compartment for degradation.
“suggest that phagosomes require Atg5 to move through the RPE and enter the lysosomal compartment for degradation.”
Quote in the paperSubstantial claim - Interpretationreasoning
Atg5-mediated phagocytic processes in the RPE are critical to the recycling of optimal amounts of retinoids.
“Atg5 mediated phagocytic processes in the RPE must be critical to the recycling of optimal amounts of retinoids.”
Quote in the paperSubstantial claim- Rests on an assumption: 9-cis RAL can substitute for 11-cis RAL to restore visual function in Atg5-deficient RPE.
- Interpretationown data
There is a direct link between deficiencies in POS degradation and the visual cycle.
“This provides a direct link between deficiencies in POS degradation and the visual cycle.”
Quote in the paperSubstantial claim- Rests on an assumption: 9-cis RAL can substitute for 11-cis RAL to restore visual function in Atg5-deficient RPE.
- Interpretationreasoning
The visual cycle and RPE phagocytosis converge.
“There is a convergence of the visual cycle and RPE phagocytosis (Graphical Abstract).”
Quote in the paperSubstantial claim - Premisecitation
Supplementation with nutritional vitamin A can improve night vision difficulties in elderly individuals.
“supplementation with nutritional vitamin A can improve this condition (Owsley et al., 2006).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Owsley et al., 2006 source
Not checked in the free run.
- Interpretationreasoning
The convergence of the visual cycle and RPE phagocytosis is consistent with a role for LAP in this process.
“and therefore consistent with a role for LAP in this process.”
Quote in the paperSubstantial claim - Interpretationown data
Many symptoms of age-related visual decline are consistent with a loss of LAP function and phagocytic activity with age.
“In light of our results showing that we can restore vision in LAP-deficient mice with retinoid supplementation suggests that many of these symptoms are consistent with a loss of LAP function and phagocytic activity with age.”
Quote in the paperSubstantial claim - Interpretationown data
Recovery of all-trans ROL for 11-cis RAL synthesis is aided by the POS phagocytosis and degradation pathway.
“Our studies show that these two critical pathways converge as the recovery of all-trans ROL for 11-cis RAL synthesis is aided by the POS phagocytosis and degradation pathway”
Quote in the paperSubstantial claim
- May combine two claims. 23
- The quote only partly states this claim. 1
- Classified as probably not a substantial claim. 12
May combine two claims.
Findingown dataGFP-LC3 punctae are readily apparent in control RPE but undetectable in Atg5ΔRPE RPE.
“In control mice expressing Atg5, GFP-LC3 punctae were readily apparent (Figure 1D, left panel arrows), however these were undetectable in Atg5ΔRPE mice (Figure 1D, right panel).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataLC3 associates with single-membrane phagosomes containing engulfed POS in an Atg5-dependent manner that requires Beclin1 but not the autophagy pre-initiation complex.
“LC3 then associated with single membrane phagosomes containing engulfed POS in an Atg5 dependent manner that required Beclin1 but not the autophagy pre-initiation complex.”
- Also stated in: § A non-canonical autophagy pathway facilitates phagosome formation and POS degradation · plain
“Upon engulfment, we noted association of LC3 with the POS (Figure 4A–E, lower left panels, arrows) and that this was dependent on several autophagy proteins as determined by silencing components of the conventional autophagy pathway.”
- Also stated in: § A non-canonical autophagy pathway facilitates phagosome formation and POS degradation · plain
“silencing of Fip200 (Figure 4C, lower right panel), Ulk1 (Figure 4D, lower right panel), or Atg13 (Figure 4E, lower right panel) had no effect on co-localization of LC3 with engulfed POS (arrowheads), nor on POS-induced LC3-II formation (Figure S2B).”
Quote in the paperSubstantial claim- Also stated in: § A non-canonical autophagy pathway facilitates phagosome formation and POS degradation · plain
May combine two claims.
Findingown dataBy 16 weeks, Atg5 expression is robust in control mice but undetectable in Atg5ΔRPE RPE cells.
“by 16 weeks Atg5 expression was robust in control mice but was undetectable in Atg5ΔRPE RPE cells confirming that we had deleted Atg5 from RPE cells.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataLC3-II is most abundant in RPE at 7:00 AM and much less abundant at 7:00 PM.
“this product of the autophagy pathway was most abundant in RPE at 7:00 AM (1 h after lights on) but much less LC3-II was observed when western blots were performed on RPE harvested at 7:00 PM (1 h into the dark cycle).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTEM of control RPE fails to reveal association of double-membrane structures with phagocytosed POS; POS are surrounded by single membranes.
“examination of control RPE by transmission electron microscopy (TEM) failed to reveal any association of double-membrane structures with phagocytosed POS (the latter were readily seen as electron dense structures in the cytoplasm surrounded by a single membranes, white arrows) (Figure 3D).”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataExogenous 9-cis RAL supplementation restored rod and cone function in Atg5ΔRPE mice.
“These mice also exhibited decreased photoreceptor responses to light stimuli and decreased chromophore levels that were restored with exogenous retinoid supplementation.”
- Also stated in: § Non-canonical autophagy in the RPE contributes to the retinoid supply for the photoreceptors · hedged
“post-treatment results indicated no significant difference in rod and cone function between the two groups (Figure 7B).”
Quote in the paperSubstantial claim- Rests on an assumption: 9-cis RAL is a functional analog of the visual chromophore 11-cis RAL.
- Also stated in: § Non-canonical autophagy in the RPE contributes to the retinoid supply for the photoreceptors · hedged
May combine two claims.
Findingown dataAll-trans retinyl-esters are not significantly different between Atg5ΔRPE and control, indicating that vitamin A delivery through the blood to the RPE is unaffected.
“All-trans retinyl-esters (RE) were not significantly different between Atg5ΔRPE and a control, indicating that vitamin A delivery through the blood to the RPE was unaffected.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSilencing Ulk1 in RPE cells has no effect on POS-induced LC3-I to LC3-II conversion but prevents conventional autophagy activated by rapamycin.
“Silencing Ulk1 in RPE cells had no effect on POS induced LC3-I to LC3-II conversion but prevented conventional autophagy activated by rapamycin (Figure S2B).”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationIn Ulk1−/− RPE, p62/SQSTM accumulates, indicating defective autophagy.
“we also observed the accumulation of p62/SQSTM [a hallmark of defective autophagy (Klionsky et al., 2012; Mizushima et al., 2010; Takamura et al., 2011)] in the Ulk1−/− RPE indicating that the enzymatic production of LC3-II was likely due to POS induced LAP as opposed to classical autophagy.”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Findingown dataSilencing of Fip200, Ulk1, or Atg13 has no effect on co-localization of LC3 with engulfed POS nor on POS-induced LC3-II formation.
“Strikingly however, silencing of Fip200 (Figure 4C, lower right panel), Ulk1 (Figure 4D, lower right panel), or Atg13 (Figure 4E, lower right panel) had no effect on co-localization of LC3 with engulfed POS (arrowheads), nor on POS-induced LC3-II formation (Figure S2B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThis movement of POS is not apparent in cells lacking Atg5; POS are located more apically at comparable time points.
“This movement of POS was not apparent in cells lacking Atg5 (Figure 5D, right) as the POS were located more apically at comparable time points to controls similar to what we observed in the Atg5ΔRPE mouse (Figure 3).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn Atg5ΔRPE mouse RPE, Lamp1 expression is reduced following RPE phagocytosis and availability of mature cathepsin D is reduced.
“This observation was supported by in vivo evidence when we examined RPE cells from the Atg5ΔRPE mouse where Lamp1 expression was reduced following RPE phagocytosis as was the availability of mature cathepsin D (Figure S3B).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationLAP is a process in which the single membranes of phagosomes directly associate with LC3.
“We previously described a process in macrophages (Martinez et al., 2011; Sanjuan et al., 2007) and plasmacytoid dendritic cells (Henault et al., 2012) in which the single membranes of phagosomes directly associate with LC3, a phenomenon we called LC3-associated phagocytosis (LAP) (Sanjuan et al., 2009).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Interpretationown dataAtg5 loss in the RPE results in diminished retinal function without a detectable decrease in the numbers of photoreceptors.
“Thus, while Atg5 loss in the RPE results in diminished retinal function there was not a detectable decrease in the numbers of photoreceptors.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationLAP is engaged by engulfment of particles that stimulate TLR-1/2, 2/6, 3, or 4, Fc-receptors, or upon engulfment of dying cells.
“LAP is engaged by the engulfment of particles that stimulate Toll-like receptors (TLR)-1/2, 2/6, 3, or 4 (Sanjuan et al., 2007), Fc-receptors (Henault et al., 2012; Huang et al., 2009), or upon engulfment of dying cells (Martinez et al., 2011).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHost defense against microbial infection involves recruitment of LC3 to phagosomes, promoting their maturation and microbial killing.
“Similarly, host defense against microbial infection involves the recruitment of LC3 to phagosomes, promoting their maturation and microbial killing (Henault et al., 2012; Huang et al., 2009).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Interpretationown dataPOS phagocytosis promotes a non-canonical form of autophagy (LAP) that is dependent on LC3 and Atg5 but is not classical autophagy which requires Ulk1, Fip200, and Atg13.
“This supports the idea that POS phagocytosis promotes a non-canonical form of autophagy (i.e. LAP) that is dependent on LC3 and Atg5 but is not classical autophagy which requires Ulk1, Fip200, and Atg13 (Martinez et al., 2011; Sanjuan et al., 2007; Sanjuan et al., 2009).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationLike conventional autophagy, LAP requires Beclin-1, Atg5, and Atg7 but proceeds independently of the autophagic pre-initiation complex, including Ulk1, Fip200/Atg17, and ATG13.
“Like conventional autophagy, LAP requires Beclin-1, Atg5, and Atg7 (Florey et al., 2011; Henault et al., 2012; Martinez et al., 2011; Sanjuan et al., 2007) but LAP proceeds independently of the autophagic pre-initiation complex, including Ulk1 (Henault et al., 2012; Martinez et al., 2011), Fip200/Atg17 (Florey et al., 2011; Henault et al., 2012), and ATG13 (Henault et al., 2012).”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationFusion of the lysosome to the phagosome in dendritic cells requires Atg5 and LC3 for efficient antigen degradation and presentation to T cells.
“In a similar manner fusion of the lysosome to the phagosome in dendritic cells required Atg5 and LC3 for efficient antigen degradation and presentation to T cells (Lee et al., 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Lee et al., 2010 source
Not checked in the free run.
May combine two claims.
Interpretationown dataBinding and engulfment of POS are independent of Atg5, but their ability to move through RPE cells and localize to the phagosome for digestion is impaired when LAP is disrupted.
“Thus, while binding and engulfment were independent of Atg5 (Figure S2C) their ability to move through the RPE cells and localize to the phagosome for digestion is impaired when LAP is disrupted.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIn macrophages, degradation of apoptotic corpses utilizes LAP to degrade apoptotic bodies and inhibit the immune response.
“In macrophages degradation of apoptotic corpses utilizes LAP as a mechanism to degrade apoptotic bodies and inhibit the immune response.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Martinez et al., 2011 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationDisruption of LAP-mediated degradation of apoptotic corpses prevents effective degradation and leads to release of pro-inflammatory cytokines.
“Disruption of this process prevented effective degradation and led to the release of pro-inflammatory cytokines (Martinez et al., 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Martinez et al., 2011 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningProteins of the visual cycle are in place but retinoid recycling might be impaired with age.
“Thus, proteins of the visual cycle are in place but retinoid recycling might be impaired with age.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe deterioration of the visual cycle with age is well-documented.
“The deterioration of the visual cycle with age is also well-documented (Gaffney et al., 2012; Kolesnikov et al., 2010)”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Gaffney et al., 2012 source
Not checked in the free run.
- cites Kolesnikov et al., 2010
Not checked in the free run.
May combine two claims.
InterpretationreasoningOnly then does the lysosome fuse to the phagosome forming the phagolysosome, leading to maturation and degradation of the ingested POS cargo.
“Only then does the lysosome fuse to the phagosome forming the phagolysosome leading to maturation and degradation of the ingested POS cargo.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe decline in autophagy with age contributes to a number of age-related diseases.
“Recent studies have suggested that the decline in autophagy with age contributes to a number of age-related diseases (Cuervo et al., 2005; Rubinsztein et al., 2011)”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenAll experiments contained at least three mice per group and were repeated a minimum of three times.
“All experiments contained at least three mice per group and were repeated a minimum of three times.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
InterpretationreasoningDegradation products are removed from the cell by transport to the choroid while some materials are recycled to the photoreceptors to replenish necessary components.
“Degradation products are then removed from the cell by transport to the choroid while some materials are recycled to the photoreceptors to replenish necessary components.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenIn all experiments, littermate control animals were used.
“In all experiments littermate control animals were used (Atg5f/+;cre+ or Atg5f/f).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationnone givenOnce engulfed, shed outer segments enter the phagosome and the Atg12-Atg5-Atg16L complex is recruited, leading to lipidation of LC3-I by PE and its recruitment to the phagosome.
“once engulfed the shed outer segments enter the phagosome and the Atg12-Atg5-Atg16L complex is recruited, leading to the lipidation of the cytosolic form of LC3 (LC3-I) by PE and its recruitment to the phagosome.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn osteoclasts, autophagy proteins Atg5, Atg7, Atg4B, and LC3 are important for generating the osteoclast ruffled border, secretory function, and bone resorption.
“In osteoclasts, proteins essential for autophagy, including Atg5, Atg7, Atg4B, and LC3, were shown to be important for generating the osteoclast ruffled border, the secretory function of osteoclasts (lysosome-membrane fusion), and bone resorption (DeSelm et al., 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites DeSelm et al., 2011 source
Not checked in the free run.
The paper relies on this without support.
9-cis RAL is a functional analog of the visual chromophore 11-cis RAL.
“Mice then received an intraperitoneal injection of 0.25 mg/animal of the 9-cis RAL, a functional analog of the visual chromophore 11-cis RAL.”
The paper relies on this without support.
The RPE takes up 11-cis RAL bound to opsin and probably other forms of retinoids from the photoreceptors through daily phagocytosis.
“Although the RPE can also take up bis-retinoids (Finnemann et al., 2002; Katz et al., 1987), 11-cis RAL bound to opsin, and probably other forms of retinoids from the photoreceptors through daily phagocytosis, little is known about how retinoid products recovered by this route affect photoreceptor function and/or survival.”
The paper relies on this without support.
The relationship of autophagy to POS phagocytosis and degradation is currently unknown.
“The relationship of autophagy to POS phagocytosis and degradation is currently unknown.”
The paper relies on this without support.
9-cis RAL can substitute for 11-cis RAL to restore visual function in Atg5-deficient RPE.
“the loss of visual function was restored by exogenous supplementation with the chromophore analog, 9-cis RAL.”
The paper relies on this without support.
The visual cycle requires 11-cis RAL for phototransduction.
“The visual cycle begins following the absorption of light by visual pigments containing 11-cis RAL, which isomerizes to the all-trans configuration.”
The paper relies on this without support.
Phagocytosis of POS tips supports photoreceptor disk renewal.
“Phagocytosis of the POS tips (left), which are shed in the early morning, supports photoreceptor disk renewal.”
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?
Following ingestion of OS membrane by the RPE, LC3B-II, its conjugation factor ATG5, and the LC3 adaptor MREG are all found on a subpopulation of OS phagosomes within 15 min of ingestion.
“Following the ingestion of OS membrane by the RPE, LC3B-II, its conjugation factor, ATG5, as well as the LC3 adaptor melanoregulin (MREG), are all found on a subpopulation of OS phagosomes within 15 min of ingestion (Kim et al., 2013; Frost et al., 2015).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Kim et al., 2013
The decrease in retinoid chromophore synthesis in Atg5ΔRPE mice suggests a functional link between ATG5 phagosome association and visual pigment recycling.
“These mice exhibit a decrease in retinoid chromophore synthesis, including 11-cis retinal, suggesting a functional link between ATG5 phagosome association and visual pigment recycling (Kim et al., 2013).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Kim et al., 2013
When GFP-LC3B is overexpressed in cultures of undifferentiated RPE-J cells or in mice, 80-90% of opsin-containing structures are GFP-LC3B-positive.
“Higher percentages of LC3B-opsin association are observed when GFP-LC3B is overexpressed in cultures of undifferentiated RPE-J cells, or, in mice, overexpressing GFP-LC3B (Kim et al., 2013); in both cases, 80–90% of opsin-containing structures are GFP-LC3B-positive.”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Kim et al., 2013
A portion of OS phagosomes in the RPE recruit microtubule-associated protein 1 light chain 3 (LC3) in a process known as LC3-associated phagocytosis (LAP).
“In addition to the phagocytic machinery discussed in the preceding section, a portion of OS phagosomes in the RPE recruit microtubule-associated protein 1 light chain 3 (LC3) in a process known as LC3-associated phagocytosis (LAP) (Kim et al., 2013; Frost et al., 2015).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Kim et al., 2013
Atg5ΔRPE mice exhibit a decrease in retinoid chromophore synthesis, including 11-cis retinal.
“These mice exhibit a decrease in retinoid chromophore synthesis, including 11-cis retinal, suggesting a functional link between ATG5 phagosome association and visual pigment recycling (Kim et al., 2013).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Kim et al., 2013
The kinetics of OS uptake and OS phagosome degradation are sensitive to the state of RPE differentiation.
“Although some studies on LAP in the RPE have been performed with undifferentiated RPE-J cells (Kim et al., 2013; Muniz-Feliciano et al., 2017), it is well-established that the kinetics of OS uptake and OS phagosome degradation are sensitive to the state of RPE differentiation.”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Kim et al., 2013
Rubicon-deficient macrophages undergo normal levels of phagocytic uptake yet fail to recruit LC3B-II to phagosomes.
“Rubicon-deficient macrophages undergo normal levels of phagocytic uptake yet fail to recruit LC3B-II to phagosomes (Kim et al., 2013; Martinez et al., 2015; Wong et al., 2018).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Kim et al., 2013
Knockdown of Rubcn prevents POS-induced LAP but does not affect GFP-LC3 puncta formation during canonical autophagy induced by rapamycin.
“Knockdown of Rubcn prevented POS-induced LAP (Fig. 1B, arrowheads, inset) but did not affect GFP-LC3 C puncta formation during canonical autophagy induced by rapamycin (Fig. 1B, bottom panels).”
From RUBCN/rubicon and EGFR regulate lysosomal degradative processes in the retinal pigment epithelium (RPE) of the eye (2017) · cites this paper as [13]
Starvation-induced autophagy prevented association of RUBCN with the phagosome and impaired POS degradation.
“Thus, while it was previously shown that the induction of autophagy with rapamycin did not affect the formation of GFP-LC3 C phagosomes 12,13 ; these new data reveal that starvation-induced autophagy prevented association of RUBCN with the phagosome and impaired POS degradation.”
From RUBCN/rubicon and EGFR regulate lysosomal degradative processes in the retinal pigment epithelium (RPE) of the eye (2017) · cites this paper as [13]
Rubcn knockdown does not affect expression of other known mediators of LAP (ATG5, BECN1, ATG4B) or canonical autophagy (ATG14, RB1CC1).
“Rubcn knockdown did not affect the expression of the other known mediators of LAP (ATG5, BECN1, ATG4B) or those of the canonical autophagy pathway (ATG14, RB1CC1) (Fig. 1A).”
From RUBCN/rubicon and EGFR regulate lysosomal degradative processes in the retinal pigment epithelium (RPE) of the eye (2017) · cites this paper as [13]
In freshly prepared RPE flat mounts from C57BL/6J mouse eyes, 75-80% of RHO+ phagosomes were positive for RUBCN at 7 AM, coinciding with the peak time of POS phagocytosis and LAP.
“In freshly prepared RPE flat mounts obtained from C57BL/6J mouse eyes we observed that 75-80% of the RHO C phagosomes were positive for RUBCN at 7 AM (Fig. 3A, upper panels, arrows) coinciding with the peak time of POS phagocytosis [8][9][10] and LAP. 13”
From RUBCN/rubicon and EGFR regulate lysosomal degradative processes in the retinal pigment epithelium (RPE) of the eye (2017) · cites this paper as [13]
LAP is necessary for optimal degradation of phagocytosed cargo in macrophages and RPE cells.
“The noncanonical autophagy pathway LC3-associated phagocytosis (LAP) is necessary for optimal degradation of phagocytosed cargo in macrophages 12 and RPE cells.13”
From RUBCN/rubicon and EGFR regulate lysosomal degradative processes in the retinal pigment epithelium (RPE) of the eye (2017) · cites this paper as [13]
Induction of autophagy significantly compromises POS degradation both in the intact eye and in culture.
“Although the induction of autophagy does not affect LAP in vitro (LAP defined as GFP-LC3 recruitment to the phagosome), 13,20 it significantly compromises POS degradation both in the intact eye and in culture.”
From RUBCN/rubicon and EGFR regulate lysosomal degradative processes in the retinal pigment epithelium (RPE) of the eye (2017) · cites this paper as [13]
A portion of POS phagosomes becomes decorated by LC3 and converges on the autophagic pathway.
“Recent studies have shown that a portion of POS phagosomes becomes decorated by LC3 and converges on the autophagic pathway (Kim et al., 2013; Frost et al., 2014), suggesting the possibility of comparable regulation for some of the POS phagosomes.”
From Microtubule motors transport phagosomes in the RPE, and lack of KLC1 leads to AMD-like pathogenesis (2015) · cites this paper as Kim et al., 2013
The RPE-J cell line is a reliable cell culture system for studying RPE LAP and phagocytosis.
“we utilized a reliable cell culture system 13,28”
From RUBCN/rubicon and EGFR regulate lysosomal degradative processes in the retinal pigment epithelium (RPE) of the eye (2017) · cites this paper as [13]
Loss of LAP results in decreased retinal function.
“with loss of LAP resulting in decreased retinal function (Kim et al., 2013)”
From Microtubule-associated protein 1 light chain 3B, (LC3B) is necessary to maintain lipid-mediated homeostasis in the retinal pigment epithelium (2018) · cites this paper as Kim et al., 2013
The RPE relies on LC3 family proteins for phagocytic clearance of ingested OS.
“These cells rely on Microtubule-Associated Protein 1 Light Chain 3 (LC3) family of proteins for phagocytic clearance of the ingested OS.”
From Microtubule-associated protein 1 light chain 3B, (LC3B) is necessary to maintain lipid-mediated homeostasis in the retinal pigment epithelium (2018) · cites this paper as Kim et al., 2013
The RPE relies on LC3 for LAP-mediated degradation of OS.
“and (2) a hybrid autophagy-phagocytosis degradative pathway termed LC3-associated phagocytosis (LAP) for degradation of OS (Kim et al., 2013; Frost et al., 2015; Martinez et al., 2015).”
From Microtubule-associated protein 1 light chain 3B, (LC3B) is necessary to maintain lipid-mediated homeostasis in the retinal pigment epithelium (2018) · cites this paper as Kim et al., 2013
LAP plays a critical role in visual pigment regeneration and phagosome degradation.
“LAP plays a critical role in visual pigment regeneration and phagosome degradation (Kim et al., 2013; Frost et al., 2015; Muniz-Feliciano et al., 2017)”
From Microtubule-associated protein 1 light chain 3B, (LC3B) is necessary to maintain lipid-mediated homeostasis in the retinal pigment epithelium (2018) · cites this paper as Kim et al., 2013
The RPE has adapted LAP to eliminate stressors, including daily ingestion of lipids and proteins in OS tips.
“The RPE has adapted LAP to eliminate stressors, including the daily ingestion of lipids and proteins in the form of OS tips (Kim et al., 2013; Frost et al., 2015; Reyes-Reveles et al., 2017).”
From Microtubule-associated protein 1 light chain 3B, (LC3B) is necessary to maintain lipid-mediated homeostasis in the retinal pigment epithelium (2018) · cites this paper as Kim et al., 2013
During OS phagocytosis, LC3B associates with ingested phagosomes, targeting them for degradation in LAP.
“During OS phagocytosis, LC3B associates with ingested phagosomes targeting them for degradation in a process known as LAP (Kim et al., 2013; Frost et al., 2014, 2015, 2017; Muniz-Feliciano et al., 2017).”
From Microtubule-associated protein 1 light chain 3B, (LC3B) is necessary to maintain lipid-mediated homeostasis in the retinal pigment epithelium (2018) · cites this paper as Kim et al., 2013
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Biological Functions of Autophagy Genes: A Disease Perspective
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Self-citationNon-canonical autophagy drives alternative ATG8 conjugation to phosphatidylserine
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- Authors
- Kim, J.-Y., Zhao, H., Martinez, J., Doggett, T. A., Kolesnikov, A. V., Tang, P. H., Ablonczy, Z., Chan, C.-C., Zhou, Z., Green, D. R., & Ferguson, T. A.
- Affiliations
- Washington University in St. Louis (US)
- St. Jude Children's Research Hospital (US)
- Medical University of South Carolina (US)
- National Institutes of Health (US)
- Corresponding author
- Green, Douglas R.
- Ferguson, Thomas A.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-07
- Volume
- 154
- Issue
- 2
- Pages
- 365-376
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3744125
- OpenAlex
- W2053670812
- Semantic Scholar
- 303489ecfc694b5a375bcf0ae15e3eda2fe5c00b
- Cited by
- 347
- References
- 68
- Citations by year
- 2026: 11 · 2025: 18 · 2024: 26 · 2023: 30 · 2022: 30 · 2021: 33 · 2020: 39 · 2019: 24 · 2018: 30 · 2017: 21 · 2016: 22 · 2015: 27 · 2014: 33 · 2013: 3
- FWCI
- 20.64
- Type
- journal article
- Language
- en
- Update notices
- erratum (2013-10-24)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (EY015570, AI40646, EY02687)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- non-canonical autophagy, visual cycle, retinal pigment epithelium, phagocytosis, LC3 lipidation, ATG5, Beclin-1, lysosomal processing, chromophores, retinal degeneration
- MeSH terms
- Beclin-1, Autophagy-Related Protein 5, Animals, Autophagy, Cattle, Lysosomes, Microtubule-Associated Proteins, Phagocytosis, Phagosomes, Retinoids, Vision, Ocular, Photoreceptor Cells, Vertebrate, Apoptosis Regulatory Proteins, Mice, Retinal Pigment Epithelium
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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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