The DOI matches its Crossref record; 42 of the 44 references it cites were found in a registry or an index; 3 of the 49 sources its claims cite were checked for support.
ADAM17 mediates ectodomain shedding of the soluble VLDL receptor fragment in the retinal epithelium
Open accessAbstract
Very low-density lipoprotein receptor (VLDLR) is a multifunctional transmembrane protein. Beyond the function of the full-length VLDLR in lipid transport, the soluble ectodomain of VLDLR (sVLDLR) confers anti-inflammatory and antiangiogenic roles in ocular tissues through inhibition of canonical Wnt signaling. However, it remains unknown how sVLDLR is shed into the extracellular space. In this study, we present the first evidence that a disintegrin and metalloprotease 17 (ADAM17) is responsible for sVLDLR shedding in human retinal pigment epithelium cells using pharmacological and genetic approaches. Among selected proteinase inhibitors, an ADAM17 inhibitor demonstrated the most potent inhibitory effect on sVLDLR shedding. siRNA-mediated knockdown or CRISPR/Cas9-mediated KO of ADAM17 diminished, whereas plasmid-mediated overexpression of ADAM17 promoted sVLDLR shedding. The amount of shed sVLDLR correlated with an inhibitory effect on the Wnt signaling pathway. Consistent with these in vitro findings, intravitreal injection of an ADAM17 inhibitor reduced sVLDLR levels in the extracellular matrix in the mouse retina. In addition, our results demonstrated that ADAM17 cleaved VLDLR only in cells coexpressing these proteins, suggesting that shedding occurs in a cis manner. Moreover, our study demonstrated that aberrant activation of Wnt signaling was associated with decreased sVLDLR levels, along with downregulation of ADAM17 in ocular tissues of an age-related macular degeneration model. Taken together, our observations reveal the mechanism underlying VLDLR cleavage and identify a potential therapeutic target for the treatment of disorders associated with dysregulation of Wnt signaling.
Overview
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Written from the paper’s full text.
TL;DR
ADAM17 is identified as the sheddase that releases the soluble VLDLR ectodomain (sVLDLR) in retinal pigment epithelium, acting in a cis manner that is inhibited by VLDLR O-glycosylation. In an AMD model, reduced ADAM17 and sVLDLR were associated with overactivated Wnt signaling.
Key findings
- Among proteinase inhibitors, the ADAM17 inhibitor GW280264x had the most potent inhibitory effect on VLDLRII shedding; GW280264x dose-dependently inhibited shedding and ADAM17 activity in primary human RPE cells.
- ADAM10 siRNA reduced ADAM10 protein by approximately 80% but did not affect VLDLR shedding, whereas ADAM17 siRNA reduced ADAM17 protein by more than 70% and markedly reduced shedding; ADAM17 overexpression promoted shedding, and CRISPR/Cas9 ADAM17 KO diminished sVLDLR to barely detectable levels.
- ADAM17 KO abolished the inhibitory effect of VLDLR overexpression on Wnt3a-induced TCF/β-catenin activity, and ADAM17 KO increased VLDLR-mediated lipid droplet accumulation and ROS generation in oleic acid–treated ARPE-19 cells.
- In vivo, intravitreal GW280264x (1.5 μl of 2 mM) significantly decreased sVLDLR in the mouse interphotoreceptor matrix; in 10-month-old Abca4−/−Rdh8−/− mice, sVLDLR and ADAM17 levels/activity were lower and phosphorylated LRP6 and nonphosphorylated β-catenin were higher than in age-matched WT mice.
Methods
- Pharmacological and genetic approaches in human primary RPE cells, ARPE-19 cells, and other cell types: proteinase inhibitors, PMA, siRNA knockdown, plasmid overexpression, and CRISPR/Cas9-mediated ADAM17 KO; shedding assessed by Western blot of conditioned media and cell lysates.
- Functional assays included TOPFLASH TCF/β-catenin luciferase reporter, ADAM17 activity assay, BODIPY lipid droplet staining, and ROS measurement; cis versus trans cleavage tested by mixing cells expressing VLDLR and/or ADAM17, and O-glycosylation tested in ldlD cells with galactose/N-acetyl-galactosamine restoration.
- In vivo studies used C57BL/6J mice for intravitreal GW280264x and Abca4−/−Rdh8−/− mice as a dry AMD model; IPM and eyecup proteins were analyzed by Western blot, and retinal sections by immunohistochemistry; statistics used t tests or ANOVA with Student–Newman–Keuls test.
Limitations
- The paper states that a trace amount of sVLDLR remained in ADAM17 KO cells and that minor involvement of another unknown sheddase cannot be ruled out; it also states that adenovirus-mediated VLDLR overexpression may not fully recapitulate physiological conditions.
- The paper states future investigation is warranted to study the fate of the remaining VLDLR C terminus, identify the cleavage site, examine O-glycosylation of VLDLR in disorders, and test whether ADAM17 overexpression ameliorates AMD phenotypes.
- Evident from the text: GW280264x is described as an ADAM17 inhibitor but also has ADAM10 inhibitory activity (IC50 = 11.5 nM for ADAM10 and 8.0 nM for ADAM17), so inhibitor-based conclusions rely on complementary genetic evidence; the AMD association is shown in a mouse model and in vitro A2E treatment rather than direct human interventional data.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
3 of 49 cited sources checked · 2 supported · 0 flagged · accuracy not yet measured
- Premisecitation
sVLDLR is naturally present in the interphotoreceptor matrix (IPM).
“Previously, we showed that soluble N-terminal ectodomain of VLDLR (sVLDLR) is naturally present in the interphotoreceptor matrix (IPM), the extracellular matrix between the photoreceptors and retinal pigment epithelium (RPE) (10).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [10] Chen, 2016, Functional differences of very-low-density lipoprotein receptor splice variants in regulating Wnt signaling, Mol. Cell. Biol. source
- Premisecitation
VLDLRII demonstrates a more potent Wnt inhibitory effect than VLDLRI.
“and thus demonstrates a more potent Wnt inhibitory effect (10).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [10] Chen, 2016, Functional differences of very-low-density lipoprotein receptor splice variants in regulating Wnt signaling, Mol. Cell. Biol. source
- Findingown data
ADAM17 is responsible for sVLDLR shedding in human retinal pigment epithelium cells.
“we present the first evidence that a disintegrin and metalloprotease 17 (ADAM17) is responsible for sVLDLR shedding in human retinal pigment epithelium cells using pharmacological and genetic approaches.”
Quote in the paperSubstantial claim - Findingown data
ADAM17 siRNA caused a marked reduction of VLDLR shedding.
“whereas there was a marked reduction of VLDLR shedding in the ADAM17 siRNA-treated cells”
Quote in the paperSubstantial claim - Findingown data
GW280264x dose dependently inhibited ADAM17 activity in primary human RPE cells.
“We also demonstrated that GW280264x dose dependently inhibited VLDLRII shedding (Fig. 1, C and D) and ADAM17 activity (Fig. 1E) in primary human RPE cells.”
Quote in the paperSubstantial claim
- Findingown data
ADAM17 cleaved VLDLR only in cells coexpressing these proteins.
“ADAM17 cleaved VLDLR only in cells coexpressing these proteins”
- Also stated in: § ADAM17 cleaved VLDLR in a cis manner, which was impeded by O-glycosylation of VLDLR · plain
“ADAM17 trans overexpression did not result in increased VLDLR shedding (Fig. 7, A and B).”
Quote in the paperSubstantial claim - Also stated in: § ADAM17 cleaved VLDLR in a cis manner, which was impeded by O-glycosylation of VLDLR · plain
- Findingown data
PMA increased VLDLRII shedding.
“we found that PMA increased VLDLRII shedding”
Quote in the paperSubstantial claim - Findingown data
The amount of shed sVLDLR correlated with an inhibitory effect on the Wnt signaling pathway.
“The amount of shed sVLDLR correlated with an inhibitory effect on the Wnt signaling pathway.”
Quote in the paperSubstantial claim - Findingown data
siRNA-mediated knockdown of ADAM17 diminished sVLDLR shedding.
“siRNA-mediated knockdown or CRISPR/Cas9-mediated KO of ADAM17 diminished, whereas plasmid-mediated overexpression of ADAM17 promoted sVLDLR shedding.”
- Also stated in: § VLDLR shedding was affected by ADAM17 expression · plain
“there was a marked reduction of VLDLR shedding in the ADAM17 siRNA-treated cells”
Quote in the paperSubstantial claim - Also stated in: § VLDLR shedding was affected by ADAM17 expression · plain
- Findingown data
GW280264x demonstrated the most potent inhibitory effect on VLDLRII shedding compared with other proteinase inhibitors.
“GW280264x demonstrated the most potent inhibitory effect on VLDLRII shedding compared with other proteinase inhibitors.”
Quote in the paperSubstantial claim - Findingown data
VLDLRII shedding was unaffected by GM6001.
“VLDLRII shedding was unaffected by GM6001, a pan-MMP inhibitor”
Quote in the paperSubstantial claim - Findingown data
GW280264x dose dependently inhibited VLDLRII shedding in primary human RPE cells.
“We also demonstrated that GW280264x dose dependently inhibited VLDLRII shedding (Fig. 1, C and D) and ADAM17 activity (Fig. 1E) in primary human RPE cells.”
Quote in the paperSubstantial claim - Findingown data
Intravitreal injection of an ADAM17 inhibitor reduced sVLDLR levels in the extracellular matrix in the mouse retina.
“intravitreal injection of an ADAM17 inhibitor reduced sVLDLR levels in the extracellular matrix in the mouse retina.”
- Also stated in: § ADAM17 functioned as the VLDLR sheddase in vivo · plain
“GW280264x significantly decreased sVLDLR levels in the IPM compared with the vehicle group.”
Quote in the paperSubstantial claim - Also stated in: § ADAM17 functioned as the VLDLR sheddase in vivo · plain
- Findingown data
VLDLRI shedding was suppressed most effectively with GW280264x relative to other sheddase inhibitors.
“we found that VLDLRI shedding was suppressed most effectively with GW280264x relative to other sheddase inhibitors (Fig. S2, A and B).”
Quote in the paperSubstantial claim - Findingown data
Plasmid-mediated overexpression of ADAM17 promoted sVLDLR shedding.
“siRNA-mediated knockdown or CRISPR/Cas9-mediated KO of ADAM17 diminished, whereas plasmid-mediated overexpression of ADAM17 promoted sVLDLR shedding.”
- Also stated in: § VLDLR shedding was affected by ADAM17 expression · plain
“overexpression of ADAM17 promoted VLDLR shedding”
Quote in the paperSubstantial claim - Also stated in: § VLDLR shedding was affected by ADAM17 expression · plain
- Findingown data
GW280264x suppressed VLDLR shedding in other cell types, including retinal cells (R28), renal cells (HEK293), and endothelial cells (HUVEC).
“we found that GW280264x suppressed VLDLR shedding in other cell types, including retinal cells (R28 cell line with a photoreceptor origin), renal cells (human embryonic kidney 293 cell line), and endothelial cells (human umbilical vein endothelial cells) (Fig. S1, A and B).”
Quote in the paperSubstantial claim - Findingown data
CRISPR/Cas9-mediated knockout of ADAM17 diminished sVLDLR shedding.
“siRNA-mediated knockdown or CRISPR/Cas9-mediated KO of ADAM17 diminished, whereas plasmid-mediated overexpression of ADAM17 promoted sVLDLR shedding.”
- Also stated in: § CRISPR/Cas9-mediated ADAM17 KO blocked VLDLR shedding and its inhibitory effect on Wnt signaling · plain
“sVLDLR released into culture media of the ADAM17 KO cells was markedly decreased and barely detected in the ADAM17 KO cells.”
Quote in the paperSubstantial claim - Also stated in: § CRISPR/Cas9-mediated ADAM17 KO blocked VLDLR shedding and its inhibitory effect on Wnt signaling · plain
- Findingown data
ADAM10 siRNA showed no effect on VLDLR shedding.
“The ADAM10 siRNA showed no effect on VLDLR shedding”
Quote in the paperSubstantial claim - Findingown data
Among selected proteinase inhibitors, an ADAM17 inhibitor demonstrated the most potent inhibitory effect on sVLDLR shedding.
“Among selected proteinase inhibitors, an ADAM17 inhibitor demonstrated the most potent inhibitory effect on sVLDLR shedding.”
- Also stated in: § Effects of a proteinase activator and various inhibitors on VLDLR shedding · boosted
“GW280264x demonstrated the most potent inhibitory effect on VLDLRII shedding compared with other proteinase inhibitors.”
Quote in the paperSubstantial claim - Also stated in: § Effects of a proteinase activator and various inhibitors on VLDLR shedding · boosted
- Findingown data
TAPI-1 markedly reduced VLDLRII shedding.
“TNFα proteinase inhibitor 1, a broad-spectrum inhibitor of MMPs and ADAMs, markedly reduced VLDLRII shedding (Fig. 1A).”
Quote in the paperSubstantial claim - Findingown data
Increased VLDLR shedding induced by plasmid-mediated overexpression of ADAM17 was impeded by ADAM17 siRNA knockdown.
“increased VLDLR shedding induced by plasmid-mediated overexpression of ADAM17 was impeded by the ADAM17 siRNA knockdown (Fig. 2E).”
Quote in the paperSubstantial claim - Findingown data
Overexpression of ADAM10 did not affect VLDLR shedding.
“While overexpression of ADAM10 did not affect VLDLR shedding”
Quote in the paperSubstantial claim - Findingown data
There were higher levels of phosphorylated LRP6 and nonphosphorylated β-catenin in the eyecups of Abca4−/−Rdh8−/− mice compared with those in age-matched WT mice.
“there were higher levels of phosphorylated LRP6 and nonphosphorylated β-catenin in the eyecups of Abca4−/−Rdh8−/− mice compared with those in age-matched WT mice”
Quote in the paperSubstantial claim - Findingown data
A2E treatment reduced protein levels of ADAM17 in a time-dependent manner.
“A2E treatment reduced protein levels of ADAM17 in a time-dependent manner (Fig. 8, C and D).”
Quote in the paperSubstantial claim - Findingown data
Loss of ADAM17 subsequently increased ROS production in ocular tissues.
“Our results showed that loss of ADAM17 promoted VLDLR-mediated lipid accumulation in the cytosol and subsequently increased ROS production in ocular tissues.”
Quote in the paperSubstantial claim - Findingown data
Upon CHX treatment, ADAM17 level was decreased in a time-dependent manner.
“Upon CHX treatment, the ADAM17 level was decreased in a time-dependent manner (Fig. 8, E and F).”
Quote in the paperSubstantial claim - Findingown data
With MG132 treatment, protein levels of ADAM17 were increased in a time-dependent manner.
“With MG132 treatment, protein levels of ADAM17 were increased in a time-dependent manner.”
Quote in the paperSubstantial claim - Findingown data
ADAM17 trans overexpression did not result in increased VLDLR shedding.
“ADAM17 trans overexpression did not result in increased VLDLR shedding (Fig. 7, A and B).”
Quote in the paperSubstantial claim - Findingown data
ADAM17 mediated VLDLR shedding in different cell types including photoreceptor cells, kidney cells, and endothelial cells.
“We verified that ADAM17 mediated VLDLR shedding in different cell types including photoreceptor cells, kidney cells, and endothelial cells (Fig. S1).”
Quote in the paperNot a substantial claim - Findingown data
GW280264x significantly decreased sVLDLR levels in the IPM compared with the vehicle group.
“GW280264x significantly decreased sVLDLR levels in the IPM compared with the vehicle group.”
Quote in the paperSubstantial claim - Findingown data
Loss of ADAM17 promoted VLDLR-mediated lipid accumulation in the cytosol.
“Our results showed that loss of ADAM17 promoted VLDLR-mediated lipid accumulation in the cytosol and subsequently increased ROS production in ocular tissues.”
Quote in the paperSubstantial claim- Rests on an assumption: The full-length VLDLR mediates lipid uptake by cells.
- Findingown data
Under MG132 treatment, there was no significant difference of ADAM17 levels between the A2E-treated group and vehicle group.
“Under MG132 treatment, there was no significant difference of ADAM17 levels between the A2E-treated group and vehicle group”
Quote in the paperSubstantial claim - Findingown data
Levels of sVLDLR in culture media correlated with protein levels of ADAM17 in cell lysates.
“Levels of sVLDLR in culture media correlated with protein levels of ADAM17 in cell lysates (Fig. 2, E and F).”
Quote in the paperSubstantial claim - Findingown data
GM6001 did not affect the levels of shed sVLDLR in culture media.
“our results showed that GM6001 did not affect the levels of shed sVLDLR in culture media”
Quote in the paperSubstantial claim - Findingown data
Oleic acid upregulated reactive oxygen species (ROS) production in a dose-dependent manner.
“Oleic acid also upregulated reactive oxygen species (ROS) production in a dose-dependent manner (Fig. S4, C and D).”
Quote in the paperNot a substantial claim - Findingown data
Knockdown or KO of ADAM17 expression abolished VLDLR shedding.
“Knockdown or KO of ADAM17 expression abolished, whereas overexpression of ADAM17 promoted VLDLR shedding (Figs. 2 and 3).”
Quote in the paperSubstantial claim - Findingown data
ADAM17-mediated cleavage of VLDLR was impeded by O-glycosylation in the ectodomain of VLDLR.
“ADAM17 only cleaved VLDLR in a cis manner, and this cleavage was impeded by O-glycosylation in the ectodomain of VLDLR (Fig. 7).”
- Also stated in: § Discussion · plain
“In addition, we found that O-glycosylation blocked VLDLR release by ADAM17.”
- Also stated in: § Discussion · plain
“The effect of overexpressed ADAM17 on VLDLR shedding was blocked by the restoration of O-glycosylation.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
ADAM17 overexpression-mediated sVLDLR shedding was blocked by restoration of O-glycosylation using d-(+)-galactose and N-acetyl-d-galactosamine.
“the ADAM17 overexpression-mediated sVLDLR shedding was blocked by restoration of O-glycosylation using d-(+)-galactose and N-acetyl-d-galactosamine”
Quote in the paperSubstantial claim - Findingown data
ADAM17 reduced ROS generation.
“ADAM17 promoted sVLDLR-mediated Wnt inhibitory effect and reduced the full-length VLDLR-mediated lipid uptake and ROS generation (Figs. 4 and 5).”
Quote in the paperSubstantial claim - Findingown data
A2E treatment significantly decreased VLDLR shedding in human RPE cells.
“A2E treatment significantly decreased the VLDLR shedding in human RPE cells.”
Quote in the paperSubstantial claim - Findingown data
ADAM17 promoted sVLDLR-mediated Wnt inhibitory effect.
“ADAM17 promoted sVLDLR-mediated Wnt inhibitory effect and reduced the full-length VLDLR-mediated lipid uptake and ROS generation (Figs. 4 and 5).”
Quote in the paperSubstantial claim - Findingown data
Abca4−/−Rdh8−/− mice showed lower ADAM17 activity in the eyecups relative to those in age-matched WT mice.
“Abca4−/−Rdh8−/− mice showed lower ADAM17 activity in the eyecups relative to those in age-matched WT mice (Fig. 9E).”
Quote in the paperSubstantial claim - Findingown data
ADAM17 only cleaved VLDLR in a cis manner.
“ADAM17 only cleaved VLDLR in a cis manner, and this cleavage was impeded by O-glycosylation in the ectodomain of VLDLR (Fig. 7).”
- Also stated in: § Discussion · boosted
“In this study, our result demonstrated that ADAM17 cleaved VLDLR expressing on the same cell as ADAM17 but not VLDLR on a different cell.”
- Also stated in: § Discussion · plain
“ADAM17 cleaved VLDLR ectodomain in a cis manner, which was inhibited by VLDLR O-glycosylation.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · boosted
- Findingown data
Overexpression of ADAM17 enhanced the inhibitory effect of VLDLR on Wnt signaling.
“Overexpression of ADAM17 enhanced the inhibitory effect of VLDLR on Wnt signaling”
Quote in the paperSubstantial claim - Findingown data
There was an increase of VLDLR shedding in ADAM17 cis group compared with control group.
“there was an increase of VLDLR shedding in ADAM17 cis group compared with control group.”
Quote in the paperSubstantial claim - Findingown data
ADAM17 KO increased BODIPY-positive area in the cytosol relative to WT ARPE-19 cells.
“ADAM17 KO increased BODIPY-positive area in the cytosol relative to WT ARPE-19 cells.”
Quote in the paperSubstantial claim - Findingown data
An AMD stressor accelerated ADAM17 degradation.
“This study also showed that an AMD stressor accelerated ADAM17 degradation and reduced VLDLR shedding (Fig. 8).”
Quote in the paperSubstantial claim - Findingown data
There was a decrease of sVLDLR levels in the IPM from 10-month-old Abca4−/−Rdh8−/− mice.
“there was a decrease of sVLDLR levels in the IPM from 10-month-old Abca4−/−Rdh8−/− mice.”
Quote in the paperSubstantial claim - Findingown data
There were significantly lower ADAM17 protein levels in the eyecups of Abca4−/−Rdh8−/− mice compared with those in age-matched WT mice.
“There were significantly lower ADAM17 protein levels in the eyecups of Abca4−/−Rdh8−/− mice compared with those in age-matched WT mice (Fig. 9, C and D).”
Quote in the paperSubstantial claim - Findingown data
The Wnt signaling inhibitory effect of Ad-VLDLR was abolished by ADAM17 KO.
“whereas the Wnt signaling inhibitory effect of Ad-VLDLR was abolished by ADAM17 KO (Fig. 4B).”
Quote in the paperSubstantial claim - Findingown data
Under oleic acid treatment, ADAM17 KO alone increased ROS production compared with WT cells.
“under the treatment of oleic acid, ADAM17 KO alone increased ROS production compared with WT cells (Fig. 5, C and D).”
Quote in the paperSubstantial claim - Findingown data
Overexpression of ADAM17 promoted VLDLR shedding.
“overexpression of ADAM17 promoted VLDLR shedding”
- Also stated in: § Discussion · plain
“Knockdown or KO of ADAM17 expression abolished, whereas overexpression of ADAM17 promoted VLDLR shedding (Figs. 2 and 3).”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
An AMD stressor reduced VLDLR shedding.
“This study also showed that an AMD stressor accelerated ADAM17 degradation and reduced VLDLR shedding (Fig. 8).”
- Also stated in: § Discussion · plain
“The ADAM17-mediated VLDLR shedding was impeded under AMD condition”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
Ad-VLDLR induced potent Wnt signaling inhibitory effect in WT ARPE-19 cells.
“Ad-VLDLR induced potent Wnt signaling inhibitory effect in WT ARPE-19 cells”
Quote in the paperSubstantial claim - Findingown data
ADAM17 cleaved both VLDLRI and VLDLRII to shed their ectodomains.
“we showed that ADAM17 cleaved both VLDLRI and VLDLRII to shed their ectodomains (Fig. 1 and Fig. S2)”
- Also stated in: § Discussion · plain
“We found that ADAM17 cleaves both variant I and variant II of VLDLR.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
A2E accelerated the decrease of ADAM17 levels relative to the vehicle group.
“A2E accelerated the decrease of ADAM17 levels relative to the vehicle group (Fig. 8, E and F).”
Quote in the paperSubstantial claim - Findingown data
ADAM17 is the VLDLR sheddase responsible for ectodomain shedding of VLDLR.
“In this study, we identified ADAM17 as the VLDLR sheddase using pharmacological and genetic approaches.”
- Also stated in: § Discussion · boosted
“By doing so in human RPE cells, we demonstrated that ADAM17 is the VLDLR sheddase responsible for ectodomain shedding of VLDLR (Fig. 11).”
- Also stated in: § Discussion · boosted
“In conclusion, the present study for the first time identified ADAM17 as VLDLR sheddase responsible for VLDLR shedding.”
Quote in the paperSubstantial claim- Rests on an assumption: The sheddase that regulates VLDLR shedding remains unknown.
- Also stated in: § Discussion · boosted
- Findingown data
Wnt3a-induced TCF/β-catenin activity was inhibited by Ad-VLDLR-mediated VLDLR overexpression.
“Wnt3a-induced T-cell factor (TCF)/β-catenin activity was inhibited by Ad-VLDLR-mediated VLDLR overexpression (Fig. 4A).”
Quote in the paperSubstantial claim - Findingown data
There was no significant difference of the full-length VLDLR in the eyecups between Abca4−/−Rdh8−/− mice and age-matched WT mice.
“There was no significant difference of the full-length VLDLR in the eyecups between Abca4−/−Rdh8−/− mice and age-matched WT mice (Fig. S6).”
Quote in the paperSubstantial claim - Findingown data
sVLDLR released into culture media of ADAM17 KO cells was markedly decreased and barely detected.
“sVLDLR released into culture media of the ADAM17 KO cells was markedly decreased and barely detected in the ADAM17 KO cells.”
Quote in the paperSubstantial claim - Findingown data
ADAM17 reduced the full-length VLDLR-mediated lipid uptake.
“ADAM17 promoted sVLDLR-mediated Wnt inhibitory effect and reduced the full-length VLDLR-mediated lipid uptake and ROS generation (Figs. 4 and 5).”
- Also stated in: § Discussion · plain
“Meanwhile, ADAM17-mediated VLDLR shedding reduces the lipid uptake through full-length VLDLR.”
Quote in the paperSubstantial claim- Rests on an assumption: The full-length VLDLR mediates lipid uptake by cells.
- Also stated in: § Discussion · plain
- Findingown data
There was a trace amount of sVLDLR in culture media of ADAM17 KO cells.
“there was a trace amount of sVLDLR in culture media of ADAM17 KO cells.”
Quote in the paperNot a substantial claim - Findingown data
Restoration of ADAM17 in a cis manner, instead of in a trans manner, increased VLDLR shedding in ADAM17 KO ARPE-19 cells.
“the restoration of ADAM17 in a cis manner, instead of in a trans manner, increased the VLDLR shedding in ADAM17 KO ARPE-19 cells (Fig. S5, A and B).”
Quote in the paperSubstantial claim - Findingown data
Oleic acid dose dependently increased lipid droplets in WT ARPE-19 cells from 100 to 400 μM.
“oleic acid dose dependently increased lipid droplets in WT ARPE-19 cells from dose range of 100 to 400 μM (Fig. S4, A and B).”
Quote in the paperNot a substantial claim - Findingown data
ADAM17 KO enhanced VLDLR-mediated ROS generation.
“ADAM17 KO enhanced VLDLR-mediated ROS generation (Fig. 5, C and D).”
Quote in the paperSubstantial claim - Premisecitation
The VLDLR ectodomain is an endogenous inhibitor of canonical Wnt signaling through binding with LRP6.
“Recently, our group identified the VLDLR ectodomain as an endogenous inhibitor of canonical Wnt signaling through binding with the Wnt coreceptor, low-density lipoprotein receptor–related protein 6 (LRP6) (6, 7).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [6] Chen, 2007, Very low density lipoprotein receptor, a negative regulator of the Wnt signaling pathway and choroidal neovascularization, J. Biol. Chem. source
- cites [7] Lee, 2014, Receptor heterodimerization as a novel mechanism for the regulation of Wnt/beta-catenin signaling, J. Cell Sci. source
- Study design and conductown data
ADAM17 siRNA induced a more than 70% reduction of ADAM17 protein levels in human RPE cells.
“the ADAM17 siRNA induced a more than 70% reduction of ADAM17 protein levels in human RPE cells.”
Quote in the paperSubstantial claim - Premisecitation
The retina expresses exclusively VLDLRII.
“While most tissues, such as the brain, kidney, and skeletal muscle, express both VLDLRI and VLDLRII, the retina expresses exclusively VLDLRII (10)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] Chen, 2016, Functional differences of very-low-density lipoprotein receptor splice variants in regulating Wnt signaling, Mol. Cell. Biol. source
- Interpretationown data
ADAM17 were possible sheddases responsible for VLDLR shedding in various cell types.
“These results suggested that ADAM17 were possible sheddases responsible for VLDLR shedding in various cell types.”
Quote in the paperSubstantial claim - Interpretationreasoning
ADAMs may be responsible for VLDLR shedding.
“and ADAMs may be responsible for VLDLR shedding (Fig. 1A).”
Quote in the paperSubstantial claim - Interpretationown data
The observations reveal the mechanism underlying VLDLR cleavage.
“Taken together, our observations reveal the mechanism underlying VLDLR cleavage”
Quote in the paperSubstantial claim - Interpretationown data
PKC activation promoted the activity of the VLDLR sheddase.
“indicating that PKC activation promoted the activity of the VLDLR sheddase (Fig. 1A).”
Quote in the paperNot a substantial claim - Interpretationown data
MMPs were not involved in VLDLR shedding.
“indicating that MMPs were not involved in VLDLR shedding”
Quote in the paperSubstantial claim - Premisecitation
Overactivated Wnt signaling was detected in the macula of patients with AMD.
“Combined with our recent work showing that overactivated Wnt signaling was detected in the macula of patients with AMD (18)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18] Tuo, 2015, Wnt signaling in age-related macular degeneration: Human macular tissue and mouse model, J. Transl. Med. source
- Study design and conductown data
ADAM10 siRNA downregulated ADAM10 protein levels by approximately 80%.
“the ADAM10 siRNA downregulated ADAM10 protein levels by approximately 80%”
Quote in the paperSubstantial claim - Interpretationown data
Shedding of VLDLR by ADAM17 occurs in a cis manner.
“suggesting that shedding occurs in a cis manner.”
- Also stated in: § ADAM17 cleaved VLDLR in a cis manner, which was impeded by O-glycosylation of VLDLR · hedged
“These results indicated that ADAM17 cleaved VLDLR only in a cis manner.”
Quote in the paperSubstantial claim - Also stated in: § ADAM17 cleaved VLDLR in a cis manner, which was impeded by O-glycosylation of VLDLR · hedged
- Premisecitation
Dysfunctional MMPs are associated with AMD in human beings.
“Recently, dysfunctional MMPs have been reported to be associated with AMD in human beings (15, 16, 17).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [15] Fritsche, 2016, A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants, Nat. Genet. source
- cites [16] Campbell, 2019, The presence of ADAMs in the eye: Exploring a promising therapeutic target for age-related macular degeneration, Invest. Ophthalmol. Vis. Sci.
- cites [17] Muliyil, 2020, ADAM17-triggered TNF signalling protects the ageing Drosophila retina from lipid droplet-mediated degeneration, EMBO J. source
- Premisecitation
Dysregulated expression of ADAMs was reported in the RPE-choroid complex of patients with AMD.
“Dysregulated expression of ADAMs was reported in the RPE–choroid complex of patients with AMD (16).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] Campbell, 2019, The presence of ADAMs in the eye: Exploring a promising therapeutic target for age-related macular degeneration, Invest. Ophthalmol. Vis. Sci.
- Interpretationreasoning
The observations identify a potential therapeutic target for disorders associated with dysregulation of Wnt signaling.
“and identify a potential therapeutic target for the treatment of disorders associated with dysregulation of Wnt signaling.”
Quote in the paperSubstantial claim - Premisecitation
Lysosomal-dependent degradation of ADAM17 has an impact on ADAM17 shedding activity.
“Last, lysosomal-dependent degradation of ADAM17 has an impact on ADAM17 shedding activity (29).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Grötzinger, 2017, Molecular insights into the multilayered regulation of ADAM17: The role of the extracellular region, Biochim. Biophys. Acta Mol. Cell Res. source
- Interpretationown data
The MMP family, at least MT1-MMP, is not involved in VLDLR shedding.
“suggesting that the MMP family, at least MT1-MMP, is not involved in VLDLR shedding.”
Quote in the paperSubstantial claim - Interpretationown data
Sheddase-mediated VLDLR shedding played an important role in modulation of Wnt signaling.
“These results strongly supported our hypothesis that sheddase-mediated VLDLR shedding played an important role in modulation of Wnt signaling.”
Quote in the paperSubstantial claim - Interpretationown data
The study cannot rule out the minor involvement of another unknown sheddase contributing to VLDLR cleavage.
“Although this trace amount of sVLDLR could arise from cell debris, our study cannot rule out the minor involvement of another unknown sheddase contributing to the VLDLR cleavage.”
Quote in the paperNot a substantial claim - Interpretationown data
A2E reduced ADAM17 levels by accelerating its protein degradation.
“These results suggested that A2E reduced ADAM17 levels by accelerating its protein degradation.”
Quote in the paperSubstantial claim - Interpretationown data
MG132 blocked A2E-induced ADAM17 degradation.
“indicating that MG132 blocked A2E-induced ADAM17 degradation (Fig. 8, G and H).”
Quote in the paperSubstantial claim - Interpretationown data
Proper regulation of ADAM17-mediated VLDLR shedding is important for homeostasis of lipid metabolism.
“These results indicated that proper regulation of ADAM17-mediated VLDLR shedding is important for homeostasis of lipid metabolism.”
Quote in the paperSubstantial claim- Rests on an assumption: The full-length VLDLR mediates lipid uptake by cells.
- Interpretationreasoning
ADAM17-mediated VLDLR shedding modulates Wnt signaling in the eyes.
“Figure 11 ADAM17-mediated VLDLR shedding modulates Wnt signaling in the eyes.”
Quote in the paperSubstantial claim - Interpretationown data
Wnt signaling has a potential role in retinal inflammation and neuronal degeneration in atrophic AMD.
“suggesting a potential role of Wnt signaling in retinal inflammation and neuronal degeneration in atrophic AMD.”
Quote in the paperSubstantial claim- Rests on an assumption: Wnt signaling in atrophic AMD condition has not been evaluated.
- Premisecitation
ADAM17 levels were reduced in the RPE of dry AMD patients compared with those of healthy controls.
“It was reported that ADAM17 levels were reduced in the RPE of dry AMD patients compared with those of healthy controls (16).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] Campbell, 2019, The presence of ADAMs in the eye: Exploring a promising therapeutic target for age-related macular degeneration, Invest. Ophthalmol. Vis. Sci.
- Interpretationown data
Deficiency of ADAM17 resulted in the decrease of VLDLR shedding under dry AMD conditions.
“These results indicated that deficiency of ADAM17 resulted in the decrease of VLDLR shedding under dry AMD conditions.”
Quote in the paperSubstantial claim - Interpretationown data
ADAM17 was the sheddase responsible for VLDLR shedding.
“these results further verified that ADAM17 was the sheddase responsible for VLDLR shedding.”
Quote in the paperSubstantial claim - Interpretationown data
Glycosylation has a negative effect on ADAM17-mediated VLDLR shedding.
“indicating that glycosylation has a negative effect on ADAM17-mediated VLDLR shedding.”
Quote in the paperSubstantial claim - Premisecitation
RPE cells have endogenous VLDLR expression.
“although RPE cells have endogenous VLDLR expression (33)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] Hu, 2008, Expression of VLDLR in the retina and evolution of subretinal neovascularization in the knockout mouse model's retinal angiomatous proliferation, Invest. Ophthalmol. Vis. Sci. source
- Interpretationown data
ADAM17 was responsible for VLDLR shedding in vivo.
“This result provided the in vivo evidence supporting that ADAM17 was responsible for VLDLR shedding.”
Quote in the paperSubstantial claim - Interpretationown data
Overactivation of Wnt signaling occurred in the eyes of Abca4−/−Rdh8−/− mice.
“suggesting overactivation of Wnt signaling in the eyes of Abca4−/−Rdh8−/− mice (Fig. 9F).”
Quote in the paperSubstantial claim - Interpretationreasoning
Impeded ADAM17-mediated VLDLR shedding contributed to overactivation of Wnt signaling in AMD.
“which contributed to overactivation of Wnt signaling in AMD.”
Quote in the paperSubstantial claim - Interpretationown data
ADAM17 is responsible for ectodomain shedding in different VLDLR variants.
“suggesting that ADAM17 is responsible for ectodomain shedding in different VLDLR variants.”
Quote in the paperSubstantial claim - Interpretationown data
ADAM17, instead of ADAM10, was the VLDLR sheddase.
“confirming that ADAM17, instead of ADAM10, was the VLDLR sheddase (Fig. 2C).”
Quote in the paperSubstantial claim - Interpretationown data
ADAM17-induced accumulation of sVLDLR in culture media conferred the inhibitory effect on Wnt signaling.
“indicating that ADAM17-induced accumulation of sVLDLR in culture media conferred the inhibitory effect on Wnt signaling (Fig. 4A).”
Quote in the paperSubstantial claim - Interpretationown data
ADAM17 was responsible for VLDLR shedding.
“indicating that ADAM17 was responsible for VLDLR shedding (Fig. 2, A and B).”
Quote in the paperSubstantial claim - Interpretationown data
ADAM17 cleaved VLDLR only in a cis manner.
“These results indicated that ADAM17 cleaved VLDLR only in a cis manner.”
Quote in the paperSubstantial claim - Interpretationreasoning
Different LDLR family members are cleaved by different sheddases.
“This explains why different LDLR family members are cleaved by different sheddases.”
Quote in the paperSubstantial claim- Rests on an assumption: LDLR and VLDLR have different peptide sequences in the juxtamembrane region.
- Premisecitation
Wnt signaling is overactivated in patients with neovascular AMD and animal models of neovascular AMD.
“Our previous studies demonstrated that Wnt signaling is overactivated in patients with neovascular AMD and animal models of neovascular AMD (18, 37).”
Quote in the paperSubstantial claim0 of 2 sources checked
- Probably not a substantial claim. 35
- It may state two separate claims as one. 22
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe shed ectodomain assumes distinct biological functions in an autocrine or paracrine manner.
“In addition to abolishing the original functions of transmembrane proteins, the shed ectodomain assumes distinct biological functions in an autocrine or a paracrine manner, such as transforming growth factor alpha and tumor necrosis factor alpha (TNFα) (11).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [11] Lichtenthaler, 2018, Proteolytic ectodomain shedding of membrane proteins in mammals-hardware, concepts, and recent developments, EMBO J. source
The section “How does shedding alter membrane protein function?” says that shedding can release biologically active TGFα and TNFα ectodomains, and explicitly describes shed TNFα acting in a paracrine manner. It does not describe autocrine action, and presents termination of a membrane protein’s function and release of an active ectodomain as different ways shedding can act, not necessarily simultaneous effects. (LLM, conf=0.86)
Experimental — accuracy not yet measured
It may state two separate claims as one.
Findingown dataBoth GI254023x and GW280264x demonstrated significant inhibitory effects on VLDLRII shedding.
“Both GI254023x and GW280264x demonstrated significant inhibitory effects on VLDLRII shedding (Fig. 1, A and B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataDownregulation of ADAM17 and reduced sVLDLR levels are associated with overactivated Wnt signaling in Abca4−/−Rdh8−/− mice (an AMD model).
“Finally, our results demonstrated that downregulation of ADAM17 was associated with reduced sVLDLR levels and aberrant activation of Wnt signaling of an AMD model (Figs. 9 and 10).”
- Also stated in: § Reduced sVLDLR levels and downregulated ADAM17 as well as overactivated Wnt signaling in a mouse model with dry AMD phenotypes · plain
“Figure 9 Reduced sVLDLR levels and downregulated ADAM17 were associated with overactivated Wnt signaling in Abca4−/−Rdh8−/−mice.”
Quote in the paperSubstantial claim- Also stated in: § Reduced sVLDLR levels and downregulated ADAM17 as well as overactivated Wnt signaling in a mouse model with dry AMD phenotypes · plain
It may state two separate claims as one.
Findingown dataDownregulated ADAM17 and overactivated Wnt signaling were present in the RPE layer of Abca4−/−Rdh8−/− mice.
“Figure 10 Downregulated ADAM17 and overactivated Wnt signaling were present in the RPE layer of Abca4−/−Rdh8−/−mice.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataA2E promoted ADAM17 degradation, which could be abolished by MG132.
“As shown in Figure 8, A2E, a common AMD stressor, promoted ADAM17 degradation, which could be abolished by MG132, the lysosomal proteinase inhibitor.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataThe ADAM17 inhibitor suppressed VLDLR shedding in vitro and in vivo.
“The ADAM17 inhibitor suppressed VLDLR shedding in vitro (Fig. 1) and in vivo (Fig. 6).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataVLDLR overexpression enhanced lipid droplet accumulation, which was promoted by ADAM17 ablation.
“VLDLR overexpression enhanced the lipid droplet accumulation, which was promoted by ADAM17 ablation.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIn ADAM17 KO cells, plasmid-mediated ADAM17 overexpression restored ADAM17 levels and shed sVLDLR into culture media.
“plasmid-mediated ADAM17 overexpression restored ADAM17 levels in cell lysates and shed sVLDLR into culture media (Fig. 3, C and D).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationVLDLR variant I is encoded by the full-length VLDLR gene and mediates more efficient VLDL uptake than VLDLR variant II.
“VLDLR variant I (VLDLRI) is encoded by the full-length VLDLR gene and mediates more efficient VLDL uptake than VLDLR variant II (VLDLRII) (9).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [9] Sakai, 2009, A neuronal VLDLR variant lacking the third complement-type repeat exhibits high capacity binding of apoE containing lipoproteins, Brain Res. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationADAMs and MMPs are two prominent families of sheddases responsible for the shedding of single-span transmembrane proteins, such as LDLR.
“A disintegrin and metalloproteinases (ADAMs) and matrix metalloproteinases (MMPs) are two prominent families of sheddases responsible for the shedding of single-span transmembrane proteins, such as LDLR (12).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Murphy, 2008, The ADAMs: Signalling scissors in the tumour microenvironment, Nat. Rev. Cancer source
Probably not a substantial claim.
PremisecitationLoss of ADAM17 promotes AMD-like phenotypes.
“In addition, the latest study showed that loss of ADAM17, one of intensively studied ADAM members, promotes AMD-like phenotypes (17).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Muliyil, 2020, ADAM17-triggered TNF signalling protects the ageing Drosophila retina from lipid droplet-mediated degeneration, EMBO J. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationVLDLR serves as the receptor for reelin and clusterin, which are involved in brain pathophysiology.
“VLDLR also serves as the receptor for reelin and clusterin, which are involved in brain pathophysiology (4, 5).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [4] Dlugosz, 2018, The Reelin receptors apolipoprotein E receptor 2 (ApoER2) and VLDL receptor, Int. J. Mol. Sci. source
- cites [5] Leeb, 2014, Clusterin is a ligand for apolipoprotein E receptor 2 (ApoER2) and very low density lipoprotein receptor (VLDLR) and signals via the Reelin-signaling pathway, J. Biol. Chem. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationVariations on TIMP3 are associated with the onset of AMD.
“Genome-wide association studies showed that variations on tissue inhibitor of metalloproteinase 3 (TIMP3) are associated with the onset of AMD (15).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] Fritsche, 2016, A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants, Nat. Genet. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationVLDLR is a multifunctional protein in the LDLR family.
“Very low-density lipoprotein receptor (VLDLR) is a multifunctional protein in the low-density lipoprotein receptor (LDLR) family (1).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Go, 2012, Low-density lipoprotein receptor (LDLR) family orchestrates cholesterol homeostasis, Yale J. Biol. Med.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationDysregulated sheddases contribute to pathological changes in human diseases.
“Dysregulated sheddases contribute to the pathological changes in human diseases (11).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] Lichtenthaler, 2018, Proteolytic ectodomain shedding of membrane proteins in mammals-hardware, concepts, and recent developments, EMBO J. source
It may state two separate claims as one.
PremisecitationVLDLRII lacks the O-linked sugar domain encoded by exon 16 and confers a higher ectodomain shedding rate than VLDLRI.
“VLDLRII lacks the O-linked sugar domain encoded by exon 16 and confers a higher ectodomain shedding rate than VLDLRI”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] Chen, 2016, Functional differences of very-low-density lipoprotein receptor splice variants in regulating Wnt signaling, Mol. Cell. Biol. source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationVLDLR mediates VLDL binding and lipid uptake in extrahepatic tissues and plays a vital role in lipoprotein metabolism.
“It is originally recognized to mediate VLDL binding and lipid uptake in extrahepatic tissues, where it plays a vital role in lipoprotein metabolism (2, 3).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [2] Argraves, 2001, Members of the low density lipoprotein receptor family control diverse physiological processes, Front. Biosci. source
- cites [3] Nguyen, 2014, Very low density lipoprotein receptor (VLDLR) expression is a determinant factor in adipose tissue inflammation and adipocyte-macrophage interaction, J. Biol. Chem. source
It may state two separate claims as one.
PremisecitationVldlr gene knockout results in Wnt signaling overactivation and subsequently pathological angiogenesis and inflammation.
“In addition, Vldlr gene KO results in Wnt signaling overactivation and subsequently pathological angiogenesis and inflammation (6, 8).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [6] Chen, 2007, Very low density lipoprotein receptor, a negative regulator of the Wnt signaling pathway and choroidal neovascularization, J. Biol. Chem. source
- cites [8] Chen, 2009, Photoreceptor degeneration and retinal inflammation induced by very low-density lipoprotein receptor deficiency, Microvasc. Res. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationA recent study showed that ADAM17-mediated cleavage was negatively affected by O-glycosylation in most substrates, especially O-glycosylation sites within four amino acid residues from the cleavage sites.
“A recent study showed that ADAM17-mediated cleavage was negatively affected by O-glycosylation in most of the substrates, especially O-glycosylation sites within four amino acid residues from the cleavage sites (31).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] Goth, 2015, A systematic study of modulation of ADAM-mediated ectodomain shedding by site-specific O-glycosylation, Proc. Natl. Acad. Sci. U. S. A. source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationOleic acid constitutes VLDL and is present in extracellular matrix in the eyes.
“oleic acid was used as it constitutes VLDL, and it is present in extracellular matrix in the eyes (22, 34).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [22] Ishikawa, 2015, Structure and function of the interphotoreceptor matrix surrounding retinal photoreceptor cells, Exp. Eye Res. source
- cites [34] Heath, 2007, Dietary fatty acids make a rapid and substantial contribution to VLDL-triacylglycerol in the fed state, Am. J. Physiol. Endocrinol. Metab. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationMT1-MMP was validated as LDLR sheddase using GM6001.
“Recently, membrane type 1 (MT1) matrix MMP was validated as LDLR sheddase using GM6001, a pan-MMP inhibitor (with the inhibition on MT1-MMP) (32).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [32] Alabi, 2021, Membrane type 1 matrix metalloproteinase promotes LDL receptor shedding and accelerates the development of atherosclerosis, Nat. Commun. source
Probably not a substantial claim.
PremisecitationA2E is accumulated in RPE cells in dry AMD patients.
“As A2E is accumulated in RPE cells in dry AMD patients”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] Kiser, 2014, Chemistry of the retinoid (visual) cycle, Chem. Rev. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationTIMP3 binds with its N terminus to ADAM17 and sterically blocks the interaction between ADAM17 and its substrates.
“Among them, TIMP3 binds with its N terminus to ADAM17 and sterically blocked the interaction between ADAM17 and its substrates (29).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Grötzinger, 2017, Molecular insights into the multilayered regulation of ADAM17: The role of the extracellular region, Biochim. Biophys. Acta Mol. Cell Res. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationA2E is commonly used as the oxidant stressor of dry AMD models in vitro.
“it is commonly used as the oxidant stressor of dry AMD models in vitro (25).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [25] Kiser, 2014, Chemistry of the retinoid (visual) cycle, Chem. Rev. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationPrevious studies demonstrated that ADAMs may act in both cis or trans manner to cleave different substrates.
“Previous studies demonstrated that ADAMs may act in both cis or trans manner to cleave different substrates (30).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Buchanan, 2017, Ectodomain shedding of the cell adhesion molecule nectin-4 in ovarian cancer is mediated by ADAM10 and ADAM17, J. Biol. Chem. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationA2E is an abnormal fluorescent condensation byproduct of the visual cycle.
“A2E, bisretinoid N-retinyl-N-retinylidene ethanolamine, is an abnormal fluorescent condensation byproduct of the visual cycle (24).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [24] Perusek, 2015, Di-retinoid-pyridinium-ethanolamine (A2E) accumulation and the maintenance of the visual cycle are independent of Atg7-mediated autophagy in the retinal pigmented epithelium, J. Biol. Chem. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThere are negative regulators that inhibit ADAM17 activities, including the prodomain of ADAM17, β-integrin, and TIMP3.
“There are negative regulators that inhibit the ADAM17 activities, including the prodomain of ADAM17, β-integrin, and TIMP3 (29).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Grötzinger, 2017, Molecular insights into the multilayered regulation of ADAM17: The role of the extracellular region, Biochim. Biophys. Acta Mol. Cell Res. source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationADAM17 is also referred to as TNFα-converting enzyme and is originally identified as a proteinase responsible for cleaving the transmembrane TNFα precursor.
“ADAM17, also referred to as TNFα-converting enzyme, is originally identified as a proteinase responsible for cleaving the transmembrane TNFα precursor (27).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [27] Moss, 1997, Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha, Nature source
It may state two separate claims as one.
Interpretationown dataVLDLR-mediated lipid uptake and ROS generation were increased by ADAM17 KO.
“these results indicated that VLDLR-mediated lipid uptake and ROS generation were increased by ADAM17 KO.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataA2E may reduce the level of ADAM17 by blocking protein synthesis or promoting protein degradation of ADAM17.
“These results suggested that A2E may reduce the level of ADAM17 by blocking protein synthesis or promoting protein degradation of ADAM17.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationAbca4−/−Rdh8−/− mice manifest phenotypes of dry AMD such as A2E accumulation within RPE, inflammation, oxidative stress, and retinal neuron degeneration.
“Abca4−/−Rdh8−/− mice manifest phenotypes of dry AMD such as A2E accumulation within RPE, inflammation, oxidative stress, and retinal neuron degeneration (26).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Maeda, 2008, Retinopathy in mice induced by disrupted all-trans-retinal clearance, J. Biol. Chem. source
It may state two separate claims as one.
InterpretationreasoningADAM17 liberates sVLDLR and enables its inhibitory effect on Wnt signaling.
“ADAM17 liberates sVLDLR and enables its inhibitory effect on Wnt signaling.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationCanonical Wnt signaling profoundly affects multiple pathophysiological processes, including inflammation, oxidative stress, and fibrosis.
“The canonical Wnt signaling profoundly affects multiple pathophysiological processes, including inflammation, oxidative stress, and fibrosis (35, 36).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationADAM17 has dozens of substrates.
“Beyond the regulation of TNFα shedding, studies showed that ADAM17 has dozens of substrates (28).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28] Gooz, 2010, ADAM-17: The enzyme that does it all, Crit. Rev. Biochem. Mol. Biol. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationRecent proteomic studies have identified a number of substrates for various sheddases, but many of them have not yet been validated under sheddase-deficient conditions or via in vivo studies.
“Recent proteomic studies have identified a number of substrates for various sheddases, but many of them have not yet been validated under sheddase-deficient conditions or via in vivo studies (11).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] Lichtenthaler, 2018, Proteolytic ectodomain shedding of membrane proteins in mammals-hardware, concepts, and recent developments, EMBO J. source
It may state two separate claims as one.
Study design and conductown dataPlasmid ADAM10 and ADAM17 increased protein levels of ADAM10 and ADAM17, respectively.
“Plasmid ADAM10 and ADAM17 increased protein levels of ADAM10 and ADAM17, respectively (Fig. 2C).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataDownregulation of ADAM17 contributed to decreased VLDLR shedding into the IPM, leading to aberrant activation of Wnt signaling in subretinal regions of AMD condition.
“Collectively, these results suggested that downregulation of ADAM17 contributed to decreased VLDLR shedding into the IPM, leading to aberrant activation of Wnt signaling in subretinal regions of AMD condition.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationAmong LDLR family members, the structure of VLDLR domains is analogous to that of LDLR, including LDLR type A repeats, epidermal growth factor-like domain, O-glycosylation domain, transmembrane anchor, and cytoplasmic domain.
“Among LDLR family members, the structure of VLDLR domains is analogous to that of LDLR, including LDLR type A repeats, epidermal growth factor–like domain, O-glycosylation domain, transmembrane anchor, and cytoplasmic domain (1).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Go, 2012, Low-density lipoprotein receptor (LDLR) family orchestrates cholesterol homeostasis, Yale J. Biol. Med.
Probably not a substantial claim.
PremisecitationWnt signaling is closely controlled by several endogenous negative regulators, such as Dkk1, kallistatin, and VLDLR.
“Given the vital role of Wnt signaling, it is closely controlled by several endogenous negative regulators, such as Dkk1, kallistatin, and VLDLR (38, 39, 40).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [38] Wang, 2015, Nanoparticle-mediated expression of a Wnt pathway inhibitor ameliorates ocular neovascularization, Arterioscler. Thromb. Vasc. Biol. source
- cites [39] Semenov, 2008, DKK1 antagonizes Wnt signaling without promotion of LRP6 internalization and degradation, J. Biol. Chem. source
- cites [40] Liu, 2013, Antiangiogenic and antineuroinflammatory effects of kallistatin through interactions with the canonical Wnt pathway, Diabetes source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenTo eliminate Rd8 mutation, Abca4−/−Rdh8−/− mice were crossbred with WT 129S1/SvlmJ to generate Abca4−/−Rdh8−/− mice without Rd8 mutation.
“To eliminate Rd8 mutation, Abca4−/−Rdh8−/− mice were crossbred with WT 129S1/SvlmJ (Jackson Laboratory) to generate Abca4−/−Rdh8−/− mice without Rd8 mutation in the 129S1/SvlmJ background.”
Quote in the paperNot a substantial claimProbably not a substantial claim. It may state two separate claims as one.
PremisecitationVLDLR sheds its soluble extracellular domain, sVLDLR, to function as an endogenous inhibitor of canonical Wnt signaling by binding with Wnt receptor, LRP6.
“Our previous studies have shown that VLDLR sheds its soluble extracellular domain, sVLDLR, to function as an endogenous inhibitor of canonical Wnt signaling by binding with Wnt receptor, LRP6.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone givenAll procedures using experimental animals strictly followed approved protocols and complied with ARVO guidelines.
“All procedures using experimental animals strictly followed the protocols approved by the Institute Animal Care and Use Committee at the University of Oklahoma Health Sciences Center. All experiments were performed to comply with the Use of Animals of Association for Research in Vision and Ophthalmology guidelines.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenA minimum of three images taken from random fields of eight replicates were used for analysis.
“A minimum of three images taken from random fields of eight replicates were used for analysis.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductreasoningThe adenovirus-mediated VLDLR overexpression system may not fully recapitulate physiological conditions.
“This system may not fully recapitulate physiological conditions.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone givenExperiments were performed at least three times separately for in vitro experiments, and at least six mice per group were used for animal experiments.
“Experiments were performed at least three times separately for in vitro experiments, and at least six mice per group were used for the animal experiments.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenThe on-target and off-target effects of designed gRNA were validated using a Surveyor mutation detection kit.
“The on-target and off-target effects of designed gRNA were validated using a Surveyor mutation detection kit (Takara Bio).”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenThe genomic DNA sequences of ADAM17 gene containing gRNA target sites were analyzed by DNA sequencing.
“Finally, the genomic DNA sequences of ADAM17 gene containing gRNA target sites were analyzed by DNA sequencing.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenAge-matched WT 129S1/SvlmJ mice were used as control for experiments involving Abca4−/−Rdh8−/− mice.
“Age-matched WT 129S1/SvlmJ mice were used as control for experiments involved in Abca4−/−Rdh8−/− mice.”
Quote in the paperNot a substantial claimProbably not a substantial claim.
Study design and conductown dataADAM17 KO efficiency was verified by Western blot analysis.
“ADAM17 KO efficiency was verified by Western blot analysis.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenA minimum of six images taken from random fields of six different mice was used for analysis.
“A minimum of six images taken from random fields of six different mice was used for analysis.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
sVLDLR in the interphotoreceptor matrix is derived from retinal pigment epithelium cells.
“the IPM, the extracellular space between retinal photoreceptor cells and RPE, plays a crucial role in maintaining the homeostasis of the retina and RPE layer (22).”
“we intended to determine if the intravitreal injection of GW280264x affects sVLDLR levels in the IPM.”
The paper relies on this without support.
The ocular ADAM17 downregulation and Wnt overactivation observed in the Abca4−/−Rdh8−/− mouse model reflect the human dry AMD condition.
“Abca4−/−Rdh8−/− mice manifest phenotypes of dry AMD such as A2E accumulation within RPE, inflammation, oxidative stress, and retinal neuron degeneration (26).”
“Collectively, these results suggested that downregulation of ADAM17 contributed to decreased VLDLR shedding into the IPM, leading to aberrant activation of Wnt signaling in subretinal regions of AMD condition.”
The paper relies on this without support.
A2E-induced ADAM17 degradation in cultured RPE cells represents the mechanism of ADAM17 downregulation in dry AMD.
“As A2E is accumulated in RPE cells in dry AMD patients, it is commonly used as the oxidant stressor of dry AMD models in vitro (25).”
“These results suggested that A2E reduced ADAM17 levels by accelerating its protein degradation.”
The paper relies on this without support.
The full-length VLDLR mediates lipid uptake by cells.
“The full-length VLDLR mediates lipid uptake by cells.”
The paper relies on this without support.
Wnt signaling in atrophic AMD condition has not been evaluated.
“However, Wnt signaling in atrophic AMD condition has not been evaluated.”
The paper relies on this without support.
The sheddase that regulates VLDLR shedding remains unknown.
“However, the sheddase that regulates VLDLR shedding remains unknown.”
The paper relies on this without support.
LDLR and VLDLR have different peptide sequences in the juxtamembrane region.
“Although LDLR and VLDLR shared highly similar ectodomain, their peptide sequences are different in the juxtamembrane region.”
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.
MG132 is identified as both a lysosomal and a proteasome inhibitor
MajorThe Discussion calls MG132 a lysosomal proteinase inhibitor, whereas the Reagents section calls it a proteasome inhibitor. These descriptions conflict in the paper's account of the ADAM17 degradation experiment.
“MG132, the lysosomal proteinase inhibitor”
“MG132 (proteasome inhibitor)”
Figure 6 gives conflicting normalization proteins
MinorThe Figure 6 caption says the Western blot shows pan-cadherin alongside VLDLR, but says VLDLR densitometry from that blot was normalized by β-actin.
“C, representative images of Western blotting of full-length VLDLR and pan-cadherin in the eyecup.”
“D, densitometry quantification of VLDLR normalized by β-actin in the eyecup in (C) (n = 3).”
Figure 8 identifies different cell types for the degradation experiment
MinorThe Results describe the A2E-treated cells used to measure ADAM17 degradation as ARPE-19 cells, while the Figure 8 caption identifies the cells in that experiment as primary human RPE cells.
“we next measured ADAM17 degradation rate in the A2E-treated ARPE-19 cells after blocking protein synthesis by cycloheximide (CHX).”
“E, representative images of Western blotting for ADAM17 in primary human RPE cells with indicated treatment and duration.”
Figure 7 identifies two different cell types for panel A
MinorThe Figure 7 caption introduces the experiment as using primary human RPE cells but identifies the panel A cell lysates as ARPE-19 cells.
“Primary human RPE cells were transfected with a plasmid expressing human ADAM17 (pADAM17) or RFP as control for 24 h.”
“A, representative images of Western blotting of sVLDLR in culture media, VLDLR, ADAM10, and ADAM17 in ARPE-19 cell lysates.”
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Metadata
- Authors
- Ma, X., Takahashi, Y., Wu, W., Liang, W., Chen, J., Chakraborty, D., Li, Y., Du, Y., Benyajati, S., & Ma, J.-X.
- Affiliations
- University of Oklahoma Health Sciences Center (US)
- Corresponding author
- Ma, Jian-Xing
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2021-10
- Volume
- 297
- Issue
- 4
- Pages
- 101185
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC8487060
- OpenAlex
- W3197135142
- Cited by
- 9
- References
- 44
- Citations by year
- 2024: 2 · 2023: 3 · 2022: 3 · 2021: 1
- FWCI
- 0.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (GM122744)
- National Eye Institute (EY021725)
- University of Oklahoma Health Sciences Center (EY012231, EY019309, EY028949, EY032930, EY032931)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Keywords
- ADAM17, VLDL receptor, ectodomain shedding, retinal pigment epithelium, Wnt signaling, cis-cleavage, age-related macular degeneration, anti-angiogenic factors, anti-inflammatory factors, intravitreal injection
- MeSH terms
- ADAM17 Protein, Protein Domains, Animals, Disease Models, Animal, Humans, Macular Degeneration, Receptors, LDL, Mice, Knockout, Mice, Retinal Pigment Epithelium, Wnt Signaling Pathway
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