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, Viktor I. Korolchuk

Research output: Contribution to journalArticle

48 Scopus citations

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.

Original languageEnglish (US)
Article number256
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Carroll, B., Otten, E. G., Manni, DI., Stefanatos, R., Menzies, F. M., Smith, G. R., Jurk, DI., Kenneth, N., Wilkinson, S., Passos, J. F., Attems, J., Veal, E. A., Teyssou, E., Seilhean, D., Millecamps, S., Eskelinen, E. L., Bronowska, A. K., Rubinsztein, D. C., Sanz, A., & Korolchuk, V. I. (2018). Oxidation of SQSTM1/p62 mediates the link between redox state and protein homeostasis. Nature communications, 9(1), [256]. https://doi.org/10.1038/s41467-017-02746-z