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

Carroll, B. et al. (2018) Oxidation of SQSTM1/p62 mediates the link between redox state and protein homeostasis. Nature Communications, 9, 256. (doi: 10.1038/s41467-017-02746-z) (PMID:29343728) (PMCID:PMC5772351)

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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.

Item Type:Articles
Additional Information:This work was funded by BBSRC (V.I.K., A.S. and J.F.P), the NIHR Newcastle Biomedical Research Centre, the Newcastle upon Tyne Hospitals NHS Charity (V.I.K.) and ERC (A.S). D.C.R is grateful for funding from the UK Dementia Research Institute (funded by the MRC, Alzheimer’s Research UK and the Alzheimer’s Society). D.J. is funded by a Newcastle University Faculty of Medical Sciences Fellowship.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Sanz Montero, Professor Alberto
Authors: Carroll, B., Otten, E. G., Manni, D., Stefanatos, R., Menzies, F. M., Smith, G. R., Jurk, D., 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., and Korolchuk, V. I.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Nature Communications
Publisher:Nature Research
ISSN:2041-1723
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Nature Communications 9:256
Publisher Policy:Reproduced under a Creative Commons License

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