p62 provides dual cytoprotection against oxidative stress in the retinal pigment epithelium.
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As a signaling hub, p62/sequestosome plays important roles in cell signaling and degradation of misfolded proteins. p62 has been implicated as an adaptor protein to mediate autophagic clearance of insoluble protein aggregates in age-related diseases, including age-related macular degeneration (AMD), which is characterized by dysfunction of the retinal pigment epithelium (RPE). Our previous studies have shown that cigarette smoke (CS) induces oxidative stress and inhibits the proteasome pathway in cultured human RPE cells, suggesting that p62-mediated autophagy may become the major route to remove impaired proteins under such circumstances. In the present studies, we found that all p62 mRNA variants are abundantly expressed and upregulated by CS induced stress in cultured human RPE cells, yet isoform1 is the major translated form. We also show that p62 silencing exacerbated the CS induced accumulation of damaged proteins, both by suppressing autophagy and by inhibiting the Nrf2 antioxidant response, which in turn, increased protein oxidation. These effects of CS and p62 reduction were further confirmed in mice exposed to CS. We found that over-expression of p62 isoform1, but not its S403A mutant, which lacks affinity for ubiquitinated proteins, reduced misfolded proteins, yet simultaneously promoted an Nrf2-mediated antioxidant response. Thus, p62 provides dual, reciprocal enhancing protection to RPE cells from environmental stress induced protein misfolding and aggregation, by facilitating autophagy and the Nrf2 mediated antioxidant response, which might be a potential therapeutic target against AMD.
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Pexophagy and mitophagy both utilize the LC3 adapter p62.
“Pexophagy and mitophagy both utilize the LC3 adapter p62”
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 Wang et al., 2014
The cytoprotective role of autophagy under stress and increased p62 likely favors pexophagy and mitophagy.
“thus the cytoprotective role of autophagy under stress and increased p62 likely favors these two LC3-dependent functions (Mitter et al., 2012; Wang et al., 2014; Song 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 Wang et al., 2014
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- Authors
- Wang, L., Cano, M., & Handa, J. T.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Handa, James T.
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 1843
- Issue
- 7
- Pages
- 1248-1258
- ISSN
- 0167-4889 (ISSN-L)
- PMC
- PMC4019388
- OpenAlex
- W2129325060
- Cited by
- 82
- References
- 51
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 2 · 2023: 5 · 2022: 5 · 2021: 10 · 2020: 8 · 2019: 6 · 2018: 11 · 2017: 11 · 2016: 9 · 2015: 6 · 2014: 3
- FWCI
- 7.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Research to Prevent Blindness
- National Eye Institute (EY14005, R01EY014005, P30EY001765, EY019904, R01EY019904)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- p62, retinal pigment epithelium, age-related macular degeneration, cigarette smoke, oxidative stress, autophagy, Nrf2 antioxidant response, protein misfolding, protein aggregation, ubiquitinated proteins, protein oxidation, proteasome inhibition
- MeSH terms
- Sequestosome-1 Protein, Animals, Autophagy, Cell Line, Epithelial Cells, Gene Expression Regulation, Humans, RNA, Messenger, Smoke, Nicotiana, Signal Transduction, Protein Folding, Oxidative Stress, Cytoprotection, Protein Isoforms, RNA, Small Interfering, Adaptor Proteins, Signal Transducing, NF-E2-Related Factor 2, Mice, Retinal Pigment Epithelium
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