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Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium
Open accessAbstract
Autophagy regulates cellular homeostasis and response to environmental stress. Within the retinal pigment epithelium (RPE) of the eye, the level of autophagy can change with both age and disease. The purpose of this study is to determine the relationship between reduced autophagy and age-related degeneration of the RPE. The gene encoding RB1CC1/FIP200 (RB1-inducible coiled-coil 1), a protein essential for induction of autophagy, was selectively knocked out in the RPE by crossing Best1-Cre mice with mice in which the Rb1cc1 gene was flanked with Lox-P sites (Rb1cc1(flox/flox)). Ex vivo and in vivo analyses, including western blot, immunohistochemistry, transmission electron microscopy, fundus photography, optical coherence tomography, fluorescein angiography, and electroretinography were performed to assess the structure and function of the retina as a function of age. Deletion of Rb1cc1 resulted in multiple autophagy defects within the RPE including decreased conversion of LC3-I to LC3-II, accumulation of autophagy-targeted precursors, and increased numbers of mitochondria. Age-dependent degeneration of the RPE occurred, with formation of atrophic patches, subretinal migration of activated microglial cells, subRPE deposition of inflammatory and oxidatively damaged proteins, subretinal drusenoid deposits, and occasional foci of choroidal neovascularization. There was secondary loss of photoreceptors overlying the degenerated RPE and reduction in the electroretinogram. These observations are consistent with a critical role of autophagy in the maintenance of normal homeostasis in the aging RPE, and indicate that disruption of autophagy leads to retinal phenotypes associated with age-related degeneration.
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TL;DR
RPE-specific deletion of the autophagy inducer RB1CC1 in mice causes progressive, age-dependent retinal pigment epithelium degeneration with AMD-like features and secondary photoreceptor loss. The findings support a critical role for canonical macroautophagy in maintaining RPE homeostasis.
Key findings
- Conditional Rb1cc1 knockout in mouse RPE reduced autophagy: decreased LC3-I to LC3-II conversion, increased SQSTM1/p62, accumulation of unprocessed phagosomes, and increased mitochondria; the overlying retina had normal RB1CC1 and equal LC3-I to LC3-II conversion.
- The RPE phenotype was age-dependent: at 2 mo Rb1cc1-CKO retinas were similar to controls by OCT/histology and ERG; at 4 mo there were small white-yellowish structures, patchy RPE atrophy, hyperreflective subretinal spots, and CD68-positive macrophage infiltration; by 8 mo there was widespread RPE disruption, vacuolization, atrophy, TJP1/ZO-1 disorganization, and increased IBA1-positive cells.
- Rb1cc1-CKO RPE showed AMD-like changes: Bruch’s membrane disruption by CD29 staining, subRPE C3 and nitrotyrosine deposition, increased autofluorescence/lipofuscin, Oil Red O lipid accumulation, SQSTM1/ubiquitin-tagged debris, and occasional histologic choroidal neovascularization.
- Secondary photoreceptor degeneration occurred despite normal photoreceptor autophagy markers: decreased outer nuclear layer thickness and progressive age-dependent reductions in photopic and scotopic ERG responses.
Methods
- ARPE-19 cells: siRNA knockdown of RB1CC1, photoreceptor outer segment feeding, bafilomycin A1 treatment, western blot, and immunofluorescence for LC3/SQSTM1.
- Mice: RPE-specific Rb1cc1-CKO generated by crossing Best1-Cre with Rb1cc1 flox/flox; controls were Rb1cc1 wt; Best1-Cre littermates. Analyzed at 2, 4, and 8 mo by western blot, immunohistochemistry, transmission electron microscopy, fundus photography, OCT, fluorescein angiography, ERG, RPE flat mounts, Oil Red O, and autofluorescence.
- Statistics: mean ± SD; two-tailed Student t test and one-way ANOVA with Bonferroni correction; Kruskal-Wallis for western blotting; significance at P < 0.05.
Limitations
- Stated: the authors cannot conclude that decreased autophagy is the primary cause of AMD; the data support dysregulation of this pathway as critical but not primary.
- Stated: they cannot definitively state that the observed vessels are of choroidal origin; neovascularization foci were infrequent, seen only on histology, with no significant hyperfluorescence on angiography.
- Stated: the data do not address the role of LC3-associated phagocytosis in processing shed outer segments. Evident: findings are from a mouse model and ARPE-19 cells, so human AMD relevance remains inferential.
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“There were decreased levels of lysosome markers, such as mature CTSD/cathepsin D and LAMP1 (Fig. 9), consistent with defective processing of intracellular debris.”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Selective deletion of Rb1cc1 results in accumulation of lipids and intracellular debris
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“We found comparable levels of phosphorylated-PTK2 (pPTK2) and phosphorylated-MAPK8/JNK1-MAPK9/JNK2 (pMAPK8/9), as well as the levels of total PTK2 and MAPK8/9, in the RPE from both experimental and littermate control mice (Fig. 2D andF).”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Conditional knockout of Rb1cc1 results in reduced autophagy activation in mouse RPE
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“Disruption of Bruch's membrane in the Rb1cc1-CKO cells was demonstrated by staining for CD29, a component of the ITGB1/integrin b-1 complex that localizes to the basal surface of the RPE and that serves as a surrogate marker for disruption of the Bruch's-RPE interface and integrity of this structure (Fig. 6A andB).”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Disruption of Bruch's memb rane and subRPE inflammation
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In the paper
“These accumulations localized primarily to the basal aspect of the RPE.”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Selective deletion of Rb1cc1 results in accumulation of lipids and intracellular debris
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“Finally, transmission electron microscopy showed increased accumulation of single-membrane phagosomelike structures in the Rb1cc1-CKO cells (Fig. 4I-K).”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Selective deletion of Rb1cc1 results in an age-dependent degeneration of the RPE
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“We did not detect any significant areas of hyperfluorescence on angiography, consistent with the self-limited nature of rodent choroidal neovascularization.”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Disruption of Bruch's memb rane and subRPE inflammation
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“Optical coherence tomography (OCT), an in vivo assessment of retinal structure and thickness (Fig. 3A andB), as well as histological analysis (Fig. 3C-F), confirm that at the age of 2 mo the outer retinas of the Rb1cc1-CKO and littermate controls were similar in appearance.”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Selective deletion of Rb1cc1 results in an age-dependent degeneration of the RPE
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“Staining with Oil Red O showed intracellular accumulation of neutral lipids (Fig. 8A-C).”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Selective deletion of Rb1cc1 results in accumulation of lipids and intracellular debris
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“We noted occasional ingrowth of vessels, as demonstrated with staining for the vascular marker IB4, from the choroid into the outer retina (red arrow), consistent with foci of neovascularization (Fig. 6C-F).”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Disruption of Bruch's memb rane and subRPE inflammation
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“The sizes of these accumulations varied, ranging from small round vesicles to large, oblong-shaped structures.”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Selective deletion of Rb1cc1 results in accumulation of lipids and intracellular debris
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“Immunofluorescence analysis showed RB1CC1 siRNA-treated ARPE-19 cells have a significantly reduced punctate pattern of LC3 staining (green), consistent with the formation of fewer autophagosomes.”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Selective deletion of Rb1cc1 results in an age-dependent degeneration of the RPE
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“There was an accumulation of oxidatively damaged proteins on the basal surface of the RPE, with a resultant inflammatory response, as demonstrated by the presence of nitrotyrosine-positive staining and C3 (complement component 3) staining, respectively (Fig. 7A-D).”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Disruption of Bruch's memb rane and subRPE inflammation
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“we detected an increased presence of IBA1-positive cells in the Rb1cc1-CKO mice even at 8 mo of age (Fig. 5G); IBA1 being a marker of activated microglial cells and consistent with the activation of an immunological response to the RPE degeneration.”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Selective deletion of Rb1cc1 results in an age-dependent degeneration of the RPE
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“We also observed markedly increased autofluorescence in the RPE of the Rb1cc1-CKO mice compared to the control animals, most likely due to accumulation of lipofuscin (Fig. 7E andF).”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Disruption of Bruch's memb rane and subRPE inflammation
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“Examination of the Rb1cc1-CKO retinas revealed small, whiteyellowish structures and areas of patchy RPE atrophy (Fig. 4A andB).”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Selective deletion of Rb1cc1 results in an age-dependent degeneration of the RPE
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“These foci were infrequently seen, and only on histology.”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Disruption of Bruch's memb rane and subRPE inflammation
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“The RPE of the Rb1cc1-CKO mice were identical to the littermate controls in terms of the RPE appearance and integrity of RPE65 staining (a RPE-specific marker indicative of normal RPE function; Fig. 3E andF).”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Selective deletion of Rb1cc1 results in an age-dependent degeneration of the RPE
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“There was also a markedly reduced level of LC3-II and a significant accumulation of SQSTM1, both consistent with defective autophagy in the RPE (Fig. 2A andB).”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Conditional knockout of Rb1cc1 results in reduced autophagy activation in mouse RPE
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“Electron microscopy showed poorly processed phagosomes and accumulation of vacuoles, presumably lipid-filled and some large enough to force an apical displacement of the melanosomes.”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Selective deletion of Rb1cc1 results in accumulation of lipids and intracellular debris
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“There were areas of RPE vacuolization as well as areas of RPE atrophy, with disorganization of the overlying retina (Fig. 5C-E).”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Selective deletion of Rb1cc1 results in an age-dependent degeneration of the RPE
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“In the overlying retina there were normal levels of RB1CC1 and equal conversion of LC3-I to LC3-II, consistent with the cell-specific nature of the autophagy gene deletion (Fig. 2D).”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Conditional knockout of Rb1cc1 results in reduced autophagy activation in mouse RPE
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“The abnormal phenotype increased in severity with increasing age, and by 8 mo there was widespread disruption of the RPE”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Selective deletion of Rb1cc1 results in an age-dependent degeneration of the RPE
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“Inhibiting autophagosome-lysosome fusion with bafilomycin A 1 showed an increase in LC3-II and SQSTM1 in the control cells, which rules out the possibility that the accumulation is due to lysosomal disruption in the absence of bafilomycin A 1 .”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Knockout of RB1CC1 in ARPE-19 cells results in loss of POS-induced autophagy
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“(G, H) Immunostaining for the Cre-recombinase (red) showed that there was no RPE degeneration in the Best1-Cre control retinas, but only in the Rb1cc1-CKO retinas where there was Cre expression.”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Disclosure of Potential Conflicts of Interest
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In the paper
“In all cases, abnormalities were only seen in the Rb1cc1-CKO mouse, and not in the Best1-Cre mouse, even in areas of Cre expression.”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Disclosure of Potential Conflicts of Interest
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In the paper
“RB1CC1 is a component of the ULK1-ATG13-RB1CC1/FIP200 complex, which is inhibited by MTOR and is an essential upstream inducer of autophagy. [26][27]7][28][29]”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Introduction
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In the paper
“Aside from the essential function of RB1CC1 in regulating autophagy in mammalian cells, it is also important in regulating a number of intracellular signaling pathways such as cell survival, differentiation, migration, proliferation, and protein synthesis. 38”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Conditional knockout of Rb1cc1 results in reduced autophagy activation in mouse RPE
What the sources say
- Not checked yetcites [38] source
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In the paper
“The model presented here demonstrates that blocking the induction of autophagy in the RPE results in many of the salient features of AMD, particularly RPE atrophy, the accumulation of lipid-filled inclusions, drusenoid deposits, abnormal accumulation of reactive oxygen species, complement activation, and occasional foci of neovascularization.”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Discussion
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In the paper
“Autophagy plays a critical role in lipid metabolism and reduces lipid toxicity in a number of animal models of disease. 68,69”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Discussion
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“For example, markers of autophagy and exosomes have been found in the RPE of aged mice as well as in drusen from cadaveric eyes from people with age-related macular degeneration (AMD), 16”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Introduction
What the sources say
- Not checked yetcites [16] source
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In the paper
“We recently reported that autophagy in the RPE is activated in a circadian rhythm, 36 with a phase-shift of several hours relative to the peak of disc shedding, consistent with the time required for normal phagocytic processing of the outer segments.”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Discussion
What the sources say
- Not checked yetcites [36] source
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In the paper
“There appeared to be normal phagocytic ingestion of the shed photoreceptor outer segments, suggesting that LAP was not affected.”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Discussion
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In the paper
“Previous studies have shown that changes in RPE autophagy correlate with both progressive age and outer retinal degeneration. [16][17]7][18][19][20][21]”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Introduction
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In the paper
“These results suggested that knocking down RB1CC1 expression in the RPE did not significantly affect the levels of nonautophagy-related RB1CC1 targets, and were consistent with the Rb1cc1-CKO having primarily a defect on autophagy and not on the PTK2 and MAPK pathways.”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Conditional knockout of Rb1cc1 results in reduced autophagy activation in mouse RPE
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In the paper
“The RPE-specific defect in autophagy and resultant RPE degeneration also causes a loss of photoreceptor cells.Since autophagy in the photoreceptors is normal in this model, presumably their death is secondary to the loss of the RPE.”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Discussion
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“Recently, Dunaief and coworkers described a mouse strain in which the Best1 promoter was used to provide RPE-specific expression of the Crerecombinase and RPE-selective loss of a loxP-flanked gene. 34”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Introduction
What the sources say
- Not checked yetcites [34] source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Due to the presence of circadian changes in autophagy levels in the RPE, 36 all collections were performed at the same time of day, 1:00 p.m.”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Tissue collection
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- Not checked yetcites [36] source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably 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 images in each individual experiment were acquired with a fixed detection gain.”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Histology and immunohistochemistry
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
“(C) Manual measurement of the ONL thickness vs. total retinal thickness confirmed the automated measurements.”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Disclosure of Potential Conflicts of Interest
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“All mice were genotyped by established methods and only those negative for mutation in the Crb1/Rd8 gene were used. 70”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Animals
What the sources say
- Not checked yetcites [70] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Photoreceptors are highly dependent on the RPE for metabolic support.
“This effect is not altogether unexpected, as the photoreceptors are highly dependent on the RPE for metabolic support.”
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
“Loss of RB1CC1, a component of the ULK complex required to initiate autophagy, was shown to cause RPE atrophy and pigmentation defects as early as 4 months of age (Yao et al., 2015).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Yao et al., 2015
In the citing paper
“Decreased autophagy led to a secondary degeneration of photoreceptors, loss of scotopic and photopic vision, subretinal inflammation (microglial activation, complement activation), and sub-RPE accumulation of oxidative stress markers in 8-month-old mice.”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Yao et al., 2015
In the citing paper
“This was accompanied by the accumulation of p62/SQSTM1, damaged mitochondria, and lipid droplets with increased autofluorescence in the RPE, all indicators of impaired autophagic flux.”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Yao et al., 2015
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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Disclosure of Potential Conflicts of Interest
“(F) This finding was also seen on OCT imaging of the retina (red arrow).”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Disclosure of Potential Conflicts of Interest
“(E, F) Staining with the vascular marker, IB4, confirms that the ingrowth contained blood vessels.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Disruption of Bruch's memb rane and subRPE inflammation
“These foci were infrequently seen, and only on histology.”
§ Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium > Disclosure of Potential Conflicts of Interest
“(F) This finding was also seen on OCT imaging of the retina (red arrow).”
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Autophagy in age-related macular degeneration
Kaarniranta, K., Błasiak, J., Liton, P. B., Boulton, M. E., Klionsky, D. J., & Sinha, D. (2022) · Autophagy · doi:10.1080/15548627.2022.2069437 · Cited by 250
Self-citationAutophagy in the eye: Development, degeneration, and aging
Boya, P., Esteban‐Martínez, L., Serrano‐Puebla, A., Gómez‐Sintes, R., & Villarejo‐Zori, B. (2016) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2016.08.001 · Cited by 236
Metadata
- Authors
- Yao, J., Jia, L., Khan, N., Lin, C., Mitter, S. K., Boulton, M. E., Dunaief, J. L., Klionsky, D. J., Guan, J.-L., Thompson, D. A., & Zacks, D. N.
- Affiliations
- University of Michigan (US)
- Indiana University School of Medicine (US)
- University of Pennsylvania (US)
- University of Cincinnati (US)
- Corresponding author
- Zacks, David N
- ORCID
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2015-06-03
- Volume
- 11
- Issue
- 6
- Pages
- 939-953
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- PMC
- PMC4502815
- OpenAlex
- W1762842507
- Semantic Scholar
- 07bce5549f84e5acb548a041638cd5c386e1a073
- Cited by
- 130
- References
- 78
- Citations by year
- 2026: 4 · 2025: 21 · 2024: 9 · 2023: 10 · 2022: 11 · 2021: 12 · 2020: 17 · 2019: 12 · 2018: 11 · 2017: 9 · 2016: 10 · 2015: 4
- FWCI
- 10.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Autophagy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Research to Prevent Blindness (EY007003)
- Arnold and Mabel Beckman Initiative for Macular Research
- National Eye Institute (R01EY020823, EY-020823, EY-007003, R01EY015240)
- National Institute of General Medical Sciences (R01GM053396)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
- Keywords
- RB1CC1, FIP200, retinal pigment epithelium, age-related degeneration, LC3 conversion, mitochondrial accumulation, microglial activation, drusen, choroidal neovascularization, photoreceptor loss, electroretinogram
- MeSH terms
- Autophagy-Related Proteins, Animals, Autophagy, Electroretinography, Epithelium, Mitochondria, Sequence Deletion, Intracellular Signaling Peptides and Proteins, Mice, Retinal Pigment Epithelium
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