Circadian and noncircadian modulation of autophagy in photoreceptors and retinal pigment epithelium
Open accessAbstract
PURPOSE: Autophagy in photoreceptors and the RPE promotes homeostasis and survival. The purpose of this study is to determine the daily pattern of changes in autophagy and factors contributing to its regulation in the outer retina. METHODS: Levels of autophagy markers in the retina and RPE were evaluated over a 24-hour period. To assess the role of phagocytosis in stimulating autophagy in the RPE, cultured RPE-J cells were incubated with isolated photoreceptor outer segments and levels of autophagy markers were measured. Electron microscopy was performed on retina sections and RPE-J cells to assess formation of double-membraned vesicles consistent with autophagosomes. RESULTS: In wild-type C57BL/6 mice maintained under normal cycling light conditions, autophagy in photoreceptor cells and the RPE exhibited a bimodal pattern of activation. In photoreceptors, shifts between light and dark evoked a sharp decrease in autophagy that was followed by a time-dependent increase. In photoreceptors, translocation of transducin and arrestin from the outer to inner segment appeared to contribute to the light-dependent upregulation of autophagy. In contrast, the cyclic variations in RPE autophagy were independent of lighting conditions, and are triggered, at least in part, by ingestion of outer segments. CONCLUSIONS: Activation of autophagy in the outer retina exhibits a bimodal pattern that correlates with shifts in transduction proteins within the photoreceptor and by circadian ingestion of outer segments in the RPE. These dynamic shifts suggest a critical role for this pathway in maintaining homeostasis, with further study needed to define the mechanisms underlying the regulation of this phenomenon.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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 2-month-old mice, peak LC3 and ATG5 expression occurs 7 h after light onset.
“In 2-month-old mice, peak LC3 and ATG5 expression occurs 7 h after light onset (Yao et al., 2014).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Yao et al., 2014
Yao et al. also observed a second peak of LC3-II expression and double-membrane autophagosome formation 5 h before light onset.
“Yao et al. also observed a second peak of LC3-II expression and double-membrane autophagosome formation 5 h before light onset (Yao et al., 2014).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Yao et al., 2014
Basal autophagy in the mouse retina exhibits a bimodal circadian pattern that is regulated by distinct mechanisms in the photoreceptors and the RPE.
“Basal autophagy in the mouse retina has been shown to exhibit a bimodal circadian pattern that is regulated by distinct mechanisms in the photoreceptors and the RPE (Yao et al., 2014).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Yao et al., 2014
The daily burst of OS phagocytosis is accompanied by an increase in LC3, levels of which fluctuate over the 12 h light/dark cycle.
“The daily burst of OS phagocytosis is accompanied by an increase in LC3, levels of which fluctuate over the 12 h light/dark cycle (Yao et al., 2014; Frost 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 Yao et al., 2014
There is a second LC3 peak 6 h after light onset.
“there is a second LC3 peak 6 h after light onset (Yao et al., 2014; Frost 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 Yao et al., 2014
Autophagy in the RPE occurs, at least in part, in response to ingestion of photoreceptor outer segments (POS).
“Autophagy in the retina pigment epithelium occurs, at least in part, in response to ingestion of photoreceptor outer segments (POS). 36”
From Deletion of autophagy inducer <i>RB1CC1</i> results in degeneration of the retinal pigment epithelium (2015) · cites this paper as [36]
Autophagy in the RPE is activated in a circadian rhythm, with a phase-shift of several hours relative to the peak of disc shedding.
“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.”
From Deletion of autophagy inducer <i>RB1CC1</i> results in degeneration of the retinal pigment epithelium (2015) · cites this paper as [36]
All collections were performed at the same time of day (1:00 p.m.) because of circadian changes in autophagy levels in the RPE.
“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.”
From Deletion of autophagy inducer <i>RB1CC1</i> results in degeneration of the retinal pigment epithelium (2015) · cites this paper as [36]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Guidelines for the use and interpretation of assays for monitoring autophagy
Klionsky, D. J., Abdalla, F. C., Abeliovich, H., Abraham, R. T., Acevedo-Arozena, A., Adeli, K., Agholme, L., Agnello, M., Agostinis, P., Aguirre-Ghiso, J. A., et al. (2012) · Autophagy · doi:10.4161/auto.19496 · Cited by 3,996 · see citing works
Self-citationThe role of autophagy during the early neonatal starvation period
Kuma, A., Hatano, M., Matsui, M., Yamamoto, A., Nakaya, H., Yoshimori, T., Ohsumi, Y., Tokuhisa, T., & Mizushima, N. (2004) · Nature · doi:10.1038/nature03029 · Cited by 2,865 · see citing works
Impairment of starvation-induced and constitutive autophagy in <i>Atg7</i> -deficient mice
Komatsu, M., Waguri, S., Ueno, T., Iwata, J., Murata, S., Tanida, I., Ezaki, J., Mizushima, N., Ohsumi, Y., Uchiyama, Y., et al. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200412022 · Cited by 2,331 · see citing works
Mammalian autophagy: core molecular machinery and signaling regulation
Yang, Z., & Klionsky, D. J. (2010) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2009.11.014 · Cited by 1,956 · see citing works
Regulation of Mammalian Autophagy in Physiology and Pathophysiology
Ravikumar, B., Sarkar, S., Davies, J. E., Futter, M., Garcı́a-Arencibia, M., Green-Thompson, Z. W., Jiménez-Sánchez, M., Korolchuk, V. I., Lichtenberg, M., Luo, S., et al. (2010) · Physiological Reviews · doi:10.1152/physrev.00030.2009 · Cited by 1,726 · see citing works
Inhibition of Macroautophagy Triggers Apoptosis
Boya, P., González‐Polo, R. A., Casares, N., Perfettini, J., Dessen, P., Larochette, N., Métivier, D., Meley, D., Souquère, S., Yoshimori, T., et al. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.3.1025-1040.2005 · Cited by 1,629 · see citing works
Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis
Sanjuan, M. A., Dillon, C. P., Tait, S. W. G., Moshiach, S., Dorsey, F., Connell, S., Komatsu, M., Tanaka, K., Cleveland, J. L., Withoff, S., et al. (2007) · Nature · doi:10.1038/nature06421 · Cited by 1,347 · see citing works
Emerging regulation and functions of autophagy
Boya, P., Reggiori, F., & Codogno, P. (2013) · Nature Cell Biology · doi:10.1038/ncb2788 · Cited by 1,216 · see citing works
Rod outer segment disk shedding in rat retina: relationship to cyclic lighting
LaVail, M. M. (1976) · Science · doi:10.1126/science.982063 · Cited by 689 · see citing works
Mattapallil, M. J., Wawrousek, E. F., Chan, C.-C., Zhao, H., Roychoudhury, J., Ferguson, T. A., & Caspi, R. R. (2012) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.12-9662 · Cited by 678 · see citing works
Wangsa-Wirawan, N. D. (2003) · Archives of Ophthalmology · doi:10.1001/archopht.121.4.547 · Cited by 546 · see citing works
Stimulation of the insulin/mTOR pathway delays cone death in a mouse model of retinitis pigmentosa
Punzo, C., Kornacker, K., & Cepko, C. L. (2008) · Nature Neuroscience · doi:10.1038/nn.2234 · Cited by 515 · see citing works
Autophagy: a regulated bulk degradation process inside cells
Yoshimori, T. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2003.07.023 · Cited by 511 · see citing works
The pleiotropic role of autophagy: from protein metabolism to bactericide
Mizushima, N. (2005) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401728 · Cited by 480 · see citing works
Phagocytosis of Retinal Rod and Cone Photoreceptors
Kevany, B. M., & Palczewski, K. (2010) · Physiology · doi:10.1152/physiol.00038.2009 · Cited by 426 · see citing works
Phototransduction in transgenic mice after targeted deletion of the rod transducin α-subunit
Calvert, P. D., Krasnoperova, N. V., Lyubarsky, A., Isayama, T., Nicolò, M., Kosaras, B., Wong, G., Gannon, K. S., Margolskee, R. F., Sidman, R. L., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.250478897 · Cited by 364 · see citing works
Wang, A. L., Lukas, T. J., Yuan, M., Du, N. Y., Tso, M. O. M., & Neufeld, A. H. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004160 · Cited by 357 · see citing works
Noncanonical autophagy promotes the visual cycle
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., et al. (2013) · Cell · doi:10.1016/j.cell.2013.06.012 · Cited by 347 · see citing works
Massive Light-Driven Translocation of Transducin between the Two Major Compartments of Rod Cells
Sokolov, M., Lyubarsky, A., Strissel, K. J., Savchenko, A. B., Govardovskii, V. I., Pugh, E. N., & Arshavsky, V. Y. (2002) · Neuron · doi:10.1016/s0896-6273(02)00636-0 · Cited by 347 · see citing works
Kaarniranta, K., Sinha, D., Blasiak, J., Kauppinen, A., Veréb, Z., Salminen, A., Boulton, M. E., & Petrovski, G. (2013) · Autophagy · doi:10.4161/auto.24546 · Cited by 326 · see citing works
Metabolic dependence of photoreceptors on the choroid in the normal and detached retina.
Linsenmeier, R. A., & Padnick‐Silver, L. (2000) · PubMed · Cited by 322 · see citing works
[8] Preparation of retinal rod outer segments
Papermaster, D. S. (1982) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(82)81010-0 · Cited by 281 · see citing works
Diurnal Expression of Transducin mRNA and Translocation of Transducin in Rods of Rat Retina
Brann, M. R., & Cohen, L. V. (1987) · Science · doi:10.1126/science.3101175 · Cited by 233 · see citing works
Light-driven translocation of signaling proteins in vertebrate photoreceptors
Calvert, P. D., Strissel, K. J., Schiesser, W. E., Pugh, E. N., & Arshavsky, V. Y. (2006) · Trends in Cell Biology · doi:10.1016/j.tcb.2006.09.001 · Cited by 224 · see citing works
Balance between autophagic pathways preserves retinal homeostasis
Rodríguez‐Muela, N., Koga, H., García‐Ledo, L., de la Villa, P., de la Rosa, E. J., Cuervo, A. M., & Boya, P. (2013) · Aging Cell · doi:10.1111/acel.12072 · Cited by 175 · see citing works
Apoptosis and Autophagy in Photoreceptors Exposed to Oxidative Stress
Kunchithapautham, K., & Rohrer, B. (2007) · Autophagy · doi:10.4161/auto.4294 · Cited by 171 · see citing works
Krohne, T. U., Stratmann, N. K., Kopitz, J., & Holz, F. G. (2010) · Experimental Eye Research · doi:10.1016/j.exer.2009.12.011 · Cited by 155 · see citing works
Light induced shift and binding of S-antigen in retinal rods
BROEKHUYSE, R. M., Tolhuizen, E. F. J., Janssen, A. P. M., & Winkens, H. J. (1985) · Current Eye Research · doi:10.3109/02713688508999993 · Cited by 153 · see citing works
Rickman, C. B., Veen, T. V., & Farber, D. B. (1988) · Experimental Eye Research · doi:10.1016/0014-4835(88)90049-8 · Cited by 152 · see citing works
Autophagy protects the retina from light-induced degeneration
Chen, Y., Sawada, O., Kohno, H., Le, Y.-Z., Subauste, C., Maeda, T., & Maeda, A. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.439935 · Cited by 152 · see citing works
Strissel, K. J., Sokolov, M., Trieu, L. H., & Arshavsky, V. Y. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.4289-05.2006 · Cited by 146 · see citing works
Transient, cyclic changes in mouse visual cell gene products during the light‐dark cycle
McGinnis, J. F., Whelan, J., & Donoso, L. A. (1992) · Journal of Neuroscience Research · doi:10.1002/jnr.490310325 · Cited by 109 · see citing works
Méndez, A., Lem, J., Simon, M. I., & Chen, J. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-08-03124.2003 · Cited by 103 · see citing works
Autophagosomes in GFP-LC3 Transgenic Mice
Mizushima, N., & Kuma, A. (2008) · Methods in molecular biology · doi:10.1007/978-1-59745-157-4_7 · Cited by 101 · see citing works
Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice.
Komatsu, M., Waguri, S., Ueno, T., et al. (2016) · Tokyo Tech Research Repository (Tokyo Institute of Technology) · Cited by 88 · see citing works
Autophagy Activation in the Injured Photoreceptor Inhibits Fas-Mediated Apoptosis
Besirli, C. G., Chinskey, N. D., Zheng, Q.-D., & Zacks, D. N. (2011) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.10-7090 · Cited by 87 · see citing works
Self-citationMertk drives myosin II redistribution during retinal pigment epithelial phagocytosis
Strick, D. J., Feng, W., & Vollrath, D. (2009) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.08-3058 · Cited by 81 · see citing works
Cho, K. S., Yoon, Y. H., Choi, J. A., Lee, S.-J., & Koh, J. (2012) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.12-9827 · Cited by 77 · see citing works
Remé, C. E., Uwe Wolfrum, B., Imsand, C., Hafezi, F., & Williams, T. P. (1999) · PubMed · Cited by 76 · see citing works
Craft, C. M., Whitmore, D. H., & Donoso, L. A. (1990) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1990.tb04927.x · Cited by 71 · see citing works
Zhang, H., Huang, W. C., Zhang, H., Zhu, X., Craft, C. M., Baehr, W., & Chen, C.-K. (2003) · PubMed · Cited by 70 · see citing works
Diurnal variation of autophagy in rod visual cells in the rat
Rem�, C., & Sulser, M. (1977) · Graefe s Archive for Clinical and Experimental Ophthalmology · doi:10.1007/bf00409832 · Cited by 68 · see citing works
Viiri, J., Hyttinen, J. M. T., Ryhänen, T., Rilla, K. J., Paimela, T., Kuusisto, E., Siitonen, A., Urtti, A. O., Salminen, A., & Kaarniranta, K. (2010) · PubMed Central · Cited by 67 · see citing works
Lipofuscin granules in human photoreceptor cells.
Iwasaki, M., & Inomata, H. (1988) · PubMed · Cited by 59 · see citing works
Endogenous Gas6 and Ca2+-channel activation modulate phagocytosis by retinal pigment epithelium
Karl, M., Kroeger, W., Wimmers, S., Milenkovic, V. M., Valtink, M., Engelmann, K., & Strauß, O. (2008) · Cellular Signalling · doi:10.1016/j.cellsig.2008.02.005 · Cited by 49 · see citing works
Kaarniranta, K. (2010) · Acta Ophthalmologica · doi:10.1111/j.1755-3768.2010.2133.x · Cited by 47 · see citing works
Autography in visual cells and pigment epithelium.
Remé, C. E. (1977) · PubMed · Cited by 43 · see citing works
Autophagy is One of the Multiple Mechanisms Active in Photoreceptor Degeneration
Kunchithapautham, K., & Rohrer, B. (2007) · Autophagy · doi:10.4161/auto.3431 · Cited by 35 · see citing works
MERTK interactions with SH2-domain proteins in the retinal pigment epithelium
Shelby, S. J., Colwill, K., Dhe-Paganon, S., Pawson, T., & Thompson, D. A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0053964 · Cited by 35 · see citing works
Self-citationCircadian rhythm of autophagy and light responses of autophagy and disk-shedding in the rat retina
Rem�, C., Aeberhard, B., & Schoch, M. (1985) · Journal of Comparative Physiology A · doi:10.1007/bf00619116 · Cited by 25 · see citing works
Loss of Diurnal Arrestin Gene Expression in rds Mutant Mouse Retinas
Agarwal, N. A., Nir, I., & Papermaster, D. S. (1994) · Experimental Eye Research · doi:10.1006/exer.1994.1189 · Cited by 13 · see citing works
Diurnal Variation of Autophagy in Rod Visual Cells in the Rat
Remé, C. E., & Sulser, M. (1977) · Current research in ophthalmic electron microscopy · doi:10.1007/978-3-642-66812-8_11 · Cited by 6 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Sanjuan MA, Dillon CP, Tait SW, et al. Toll-like receptor signaling inmacrophages links the autophagy pathway to phagocytosis. Nature. 2007;450:1253-1257.
Cited by
Sorted by citations
The cell biology of the retinal pigment epithelium
Lakkaraju, A., Umapathy, A., Tan, L. X., Daniele, L., Philp, N. J., Boesze-Battaglia, K., & Williams, D. S. (2020) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100846 · Cited by 422 · see citing works
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., et al. (2015) · Autophagy · doi:10.1080/15548627.2015.1041699 · Cited by 130 · see citing works
Self-citationToops, K. A., Tan, L. X., Jiang, Z., Radu, R. A., & Lakkaraju, A. (2015) · Molecular Biology of the Cell · doi:10.1091/mbc.e14-05-1028 · Cited by 105 · see citing works
Notomi, S., Ishihara, K., Efstathiou, N. E., Lee, J.-J., Hisatomi, T., Tachibana, T., Konstantinou, E. K., Ueta, T., Murakami, Y., Maidana, D. E., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1906643116 · Cited by 92 · see citing works
Frost, L. S., Lopes, V. S., Bragin, A., Reyes-Reveles, J., Brancato, J., Cohen, A., Mitchell, C. H., Williams, D. S., & Boesze-Battaglia, K. (2015) · Molecular Neurobiology · doi:10.1007/s12035-014-8920-5 · Cited by 63 · see citing works
Sethna, S., Chamakkala, T., Gu, X., Thompson, T. C., Cao, G., Elliott, M. H., & Finnemann, S. C. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.687004 · Cited by 53 · see citing works
Dhingra, A., Bell, B. A., Peachey, N. S., Daniele, L. L., Reyes-Reveles, J., Sharp, R. C., Jun, B., Bazan, N. G., Sparrow, J. R., Kim, H. J., et al. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00351 · Cited by 41 · see citing works
- Authors
- Yao, J., Jia, L., Shelby, S. J., Ganios, A. M., Feathers, K., Thompson, D. A., & Zacks, D. N.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Zacks, David N.
- Venue
- Investigative Opthalmology & Visual Science
- Published
- 2014-05-27
- Volume
- 55
- Issue
- 5
- Pages
- 3237
- ISSN
- 0146-0404 (ISSN-L)
- 1552-5783
- PMC
- PMC4037936
- OpenAlex
- W2012171955
- Cited by
- 68
- References
- 52
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 4 · 2023: 2 · 2022: 3 · 2021: 11 · 2020: 9 · 2019: 7 · 2018: 7 · 2017: 5 · 2016: 5 · 2015: 6 · 2014: 4
- FWCI
- 5.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Investigative Ophthalmology & Visual Science (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Research to Prevent Blindness (EY007003)
- Yale University
- National Eye Institute (R01EY020823, EY-020823, EY-007003, F31EY007003, P30EY007003)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- autophagy, circadian rhythm, photoreceptors, retinal pigment epithelium, photoreceptor outer segment phagocytosis, arrestin, light-dark cycle, autophagosomes
- MeSH terms
- Animals, Autophagy, Cells, Cultured, Circadian Rhythm, Homeostasis, Mice, Inbred C57BL, Microscopy, Electron, Signal Transduction, Photoreceptor Cells, Vertebrate, Mice, Retinal Pigment Epithelium
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
