Oxidation of SQSTM1/p62 mediates the link between redox state and protein homeostasis

Bernadette Carroll, Elsje G. Otten, Diego Manni, Rhoda Stefanatos, Fiona M. Menzies, Graham R. Smith, Diana Jurk, Niall Kenneth, Simon Wilkinson, Joao F. Passos, Johannes Attems, Elizabeth A. Veal, Elisa Teyssou, Danielle Seilhean, Stéphanie Millecamps, Eeva-Liisa Eskelinen, Agnieszka K. Bronowska, David C. Rubinsztein, Alberto Sanz and Viktor I. Korolchuk ()
Additional contact information
Bernadette Carroll: Newcastle University
Elsje G. Otten: Newcastle University
Diego Manni: Newcastle University
Rhoda Stefanatos: Newcastle University
Fiona M. Menzies: Wellcome Trust/MRC Building
Graham R. Smith: Newcastle University
Diana Jurk: Newcastle University
Niall Kenneth: Newcastle University
Simon Wilkinson: University of Edinburgh
Joao F. Passos: Newcastle University
Johannes Attems: Newcastle University
Elizabeth A. Veal: Newcastle University
Elisa Teyssou: Hôpital Pitié-Salpêtrière
Danielle Seilhean: Hôpital Pitié-Salpêtrière
Stéphanie Millecamps: Hôpital Pitié-Salpêtrière
Eeva-Liisa Eskelinen: University of Helsinki
Agnieszka K. Bronowska: Newcastle University
David C. Rubinsztein: Wellcome Trust/MRC Building
Alberto Sanz: Newcastle University
Viktor I. Korolchuk: Newcastle University

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract Cellular homoeostatic pathways such as macroautophagy (hereinafter autophagy) are regulated by basic mechanisms that are conserved throughout the eukaryotic kingdom. However, it remains poorly understood how these mechanisms further evolved in higher organisms. Here we describe a modification in the autophagy pathway in vertebrates, which promotes its activity in response to oxidative stress. We have identified two oxidation-sensitive cysteine residues in a prototypic autophagy receptor SQSTM1/p62, which allow activation of pro-survival autophagy in stress conditions. The Drosophila p62 homologue, Ref(2)P, lacks these oxidation-sensitive cysteine residues and their introduction into the protein increases protein turnover and stress resistance of flies, whereas perturbation of p62 oxidation in humans may result in age-related pathology. We propose that the redox-sensitivity of p62 may have evolved in vertebrates as a mechanism that allows activation of autophagy in response to oxidative stress to maintain cellular homoeostasis and increase cell survival.

Date: 2018
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DOI: 10.1038/s41467-017-02746-z

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