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

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Carroll, Bernadette 
Otten, Elsje G 
Manni, Diego 
Stefanatos, Rhoda 
Menzies, Fiona M 


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.



Amino Acid Sequence, Animals, Autophagy, Cell Survival, Cells, Cultured, Drosophila melanogaster, HEK293 Cells, HeLa Cells, Humans, Hydrogen Peroxide, Mice, Knockout, Oxidants, Oxidation-Reduction, Proteostasis, Reactive Oxygen Species, Sequence Homology, Amino Acid, Sequestosome-1 Protein

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Nat Commun

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Springer Science and Business Media LLC