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Cited by 79Autophagy in Disease and TherapyUbiquitin and proteasome pathwaysRedox biology and oxidative stress

Induction of Covalently Crosslinked p62 Oligomers with Reduced Binding to Polyubiquitinated Proteins by the Autophagy Inhibitor Verteporfin

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Donohue, Elizabeth, Balgi, Aruna D., Komatsu, Masaaki, Roberge, Michel·2014·PLoS ONE
DOI 10.1371/journal.pone.0114964PMC PMC4262463
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Abstract

Autophagy is a cellular catabolic process responsible for the degradation of cytoplasmic constituents, including organelles and long-lived proteins, that helps maintain cellular homeostasis and protect against various cellular stresses. Verteporfin is a benzoporphyrin derivative used clinically in photodynamic therapy to treat macular degeneration. Verteporfin was recently found to inhibit autophagosome formation by an unknown mechanism that does not require exposure to light. We report that verteporfin directly targets and modifies p62, a scaffold and adaptor protein that binds both polyubiquitinated proteins destined for degradation and LC3 on autophagosomal membranes. Western blotting experiments revealed that exposure of cells or purified p62 to verteporfin causes the formation of covalently crosslinked p62 oligomers by a mechanism involving low-level singlet oxygen production. Rose bengal, a singlet oxygen producer structurally unrelated to verteporfin, also produced crosslinked p62 oligomers and inhibited autophagosome formation. Co-immunoprecipitation experiments demonstrated that crosslinked p62 oligomers retain their ability to bind to LC3 but show defective binding to polyubiquitinated proteins. Mutations in the p62 PB1 domain that abolish self-oligomerization also abolished crosslinked oligomer formation. Interestingly, small amounts of crosslinked p62 oligomers were detected in untreated cells, and other groups noted the accumulation of p62 forms with reduced SDS-PAGE mobility in cellular and animal models of oxidative stress and aging. These data indicate that p62 is particularly susceptible to oxidative crosslinking and lead us to propose a model whereby oxidized crosslinked p62 oligomers generated rapidly by drugs like verteporfin or over time during the aging process interfere with autophagy.

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  • There is not enough evidence to associate higher molecular forms induced by VP as a direct posttranslational modification.

    “There is not enough evidence to associate higher molecular forms induced by VP, as a direct posttranslational modification [47, 49].”

    From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [47]

    The Results section (‘Production of high-molecular weight p62 in vitro’; page unavailable) says the VP-induced high-molecular-weight forms are consistent with a chemical modification, not merely a conformational change or oligomerization. Another Results section (‘Verteporfin-mediated high-MW p62 is due to protein oxidation by singlet oxygen’; page unavailable) describes substantial evidence for oxidative crosslinking. The paper therefore makes the contrary point: it links these forms to a chemical modification of p62. (LLM, conf=0.88)

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  • VP is a photoresist, promoting protein crosslinking by generating free oxygen radicals.

    “There is evidence that VP is a photoresist, promoting protein crosslinking by generating free oxygen radicals [47].”

    From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [47]

    The Results section ('Verteporfin-mediated high-MW p62 is due to protein oxidation by singlet oxygen') says verteporfin produces singlet oxygen and explains how oxidation products form protein crosslinks. The paper does not call verteporfin a 'photoresist,' and its proposed mediator is singlet oxygen, not free oxygen radicals. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • VP inhibitors presented an important nonspecific effect by promoting protein crosslinking at > 1 μm.

    “Similarly, VP inhibitors presented an important nonspecific effect by promoting protein crosslinking at > 1 μm [47].”

    From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [47]

    The Introduction and Results report that verteporfin promotes covalent crosslinking of p62, including in experiments using 10 µM verteporfin. They do not establish crosslinking as a nonspecific effect or identify a threshold above 1 µM; the paper focuses on p62 oligomers. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Sorted by citations

Authors
Donohue, E., Balgi, A. D., Komatsu, M., & Roberge, M.
Affiliations
  • University of British Columbia (CA)
  • Tokyo Metropolitan Institute of Medical Science (JP)
Corresponding author
Roberge, Michel
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2014-12-10
Volume
9
Issue
12
Pages
e114964
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0114964
PMC
PMC4262463
OpenAlex
W2068689727
Cited by
79
References
9
Citations by year
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FWCI
4.04
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • University of British Columbia
  • Canadian Cancer Society Research Institute
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
verteporfin, p62, autophagy inhibition, covalent cross-linking, protein oligomerization, polyubiquitinated proteins, PB1 domain, singlet oxygen, oxidative stress, aging, autophagosome formation, photodynamic therapy
MeSH terms
Autophagosomes, Verteporfin, Autophagy, Humans, Microscopy, Fluorescence, Phagosomes, Porphyrins, Recombinant Proteins, Rose Bengal, Proto-Oncogene Proteins c-myc, Ubiquitination, MCF-7 Cells

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