The DOI matches its Crossref record; 69 of the 69 references it cites were found in a registry or an index; none of the 42 sources its claims cite is checked for support yet.
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.
Overview
AI snapshot
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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In the paper
“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.”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > Activity of the autophagy pathway is cyclically engaged in the RPE
What the sources say
- Not checked yetcites Klionsky et al., 2012 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > Retinal function decreases in Atg5ΔRPE mice
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Non-canonical Autophagy Promotes the Visual Cycle > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Non-canonical autophagy in the RPE contributes to the retinoid supply for the photoreceptors · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Further, the appearance of LC3-II in the RPE of adult mice was strikingly diminished in Atg5ΔRPE mice at this time (Figure 1B).”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > Activity of the autophagy pathway is cyclically engaged in the RPE
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Non-canonical Autophagy Promotes the Visual Cycle > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Retinal function decreases in Atg5ΔRPE mice · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > Atg5 and LC3 associate with single-membrane phagosomes containing POS
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“at 16 weeks Atg5ΔRPE mice exhibited significantly decreased rod response to brighter light stimuli compared to their littermate controls (Figure 2B).”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > Retinal function decreases in Atg5ΔRPE mice
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Non-canonical Autophagy Promotes the Visual Cycle > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Atg5 and LC3 associate with single-membrane phagosomes containing POS · hedged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > Atg5 and LC3 associate with single-membrane phagosomes containing POS
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > Activity of the autophagy pathway is cyclically engaged in the RPE
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
- It may state two separate claims as one. 23
- The quote only partly states this claim. 1
- Probably not a substantial claim. 12
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > Activity of the autophagy pathway is cyclically engaged in the RPE
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Non-canonical Autophagy Promotes the Visual Cycle > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § A non-canonical autophagy pathway facilitates phagosome formation and POS degradation · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > Activity of the autophagy pathway is cyclically engaged in the RPE
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > Activity of the autophagy pathway is cyclically engaged in the RPE
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > Atg5 and LC3 associate with single-membrane phagosomes containing POS
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Non-canonical Autophagy Promotes the Visual Cycle > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe quote only partly states this 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
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > Non-canonical autophagy in the RPE contributes to the retinoid supply for the photoreceptors
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > A non-canonical autophagy pathway facilitates phagosome formation and POS degradation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > A non-canonical autophagy pathway facilitates phagosome formation and POS degradation
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > A non-canonical autophagy pathway facilitates phagosome formation and POS degradation
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > A non-canonical autophagy pathway facilitates phagosome formation and POS degradation
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > A non-canonical autophagy pathway facilitates phagosome formation and POS degradation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > A non-canonical autophagy pathway facilitates phagosome formation and POS degradation
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, while Atg5 loss in the RPE results in diminished retinal function there was not a detectable decrease in the numbers of photoreceptors.”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > Retinal function decreases in Atg5ΔRPE mice
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > A non-canonical autophagy pathway facilitates phagosome formation and POS degradation
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Non-canonical Autophagy Promotes the Visual Cycle > DISCUSSION
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > A non-canonical autophagy pathway facilitates phagosome formation and POS degradation
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > A non-canonical autophagy pathway facilitates phagosome formation and POS degradation
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Non-canonical Autophagy Promotes the Visual Cycle > DISCUSSION
What the sources say
- Not checked yetcites Lee et al., 2010 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Non-canonical Autophagy Promotes the Visual Cycle > RESULTS > A non-canonical autophagy pathway facilitates phagosome formation and POS degradation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“In macrophages degradation of apoptotic corpses utilizes LAP as a mechanism to degrade apoptotic bodies and inhibit the immune response.”
§ Non-canonical Autophagy Promotes the Visual Cycle > DISCUSSION
What the sources say
- Not checked yetcites Martinez et al., 2011 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Disruption of this process prevented effective degradation and led to the release of pro-inflammatory cytokines (Martinez et al., 2011).”
§ Non-canonical Autophagy Promotes the Visual Cycle > DISCUSSION
What the sources say
- Not checked yetcites Martinez et al., 2011 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, proteins of the visual cycle are in place but retinoid recycling might be impaired with age.”
§ Non-canonical Autophagy Promotes the Visual Cycle > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The deterioration of the visual cycle with age is also well-documented (Gaffney et al., 2012; Kolesnikov et al., 2010)”
§ Non-canonical Autophagy Promotes the Visual Cycle > DISCUSSION
What the sources say
- Not checked yetcites Gaffney et al., 2012 source
- Not checked yetcites Kolesnikov et al., 2010
Strength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Only then does the lysosome fuse to the phagosome forming the phagolysosome leading to maturation and degradation of the ingested POS cargo.”
§ Non-canonical Autophagy Promotes the Visual Cycle > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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)”
§ Non-canonical Autophagy Promotes the Visual Cycle > DISCUSSION
What the sources say
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All experiments contained at least three mice per group and were repeated a minimum of three times.”
§ Non-canonical Autophagy Promotes the Visual Cycle > EXPERIMENTAL PROCEDURES > Mice
Strength:plain· not yet calibratedn = 3Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Non-canonical Autophagy Promotes the Visual Cycle > DISCUSSION
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In all experiments littermate control animals were used (Atg5f/+;cre+ or Atg5f/f).”
§ Non-canonical Autophagy Promotes the Visual Cycle > EXPERIMENTAL PROCEDURES > Mice
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Non-canonical Autophagy Promotes the Visual Cycle > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Non-canonical Autophagy Promotes the Visual Cycle > DISCUSSION
What the sources say
- Not checked yetcites DeSelm et al., 2011 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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?
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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 the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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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Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Ophthalmology › 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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