Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-02746-z
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Funding
- BBSRC
- NIHR Newcastle Biomedical Research Centre
- Newcastle upon Tyne Hospitals NHS Charity
- ERC
- UK Dementia Research Institute - MRC
- UK Dementia Research Institute - Alzheimer's Research UK
- UK Dementia Research Institute - Alzheimer's Society
- Newcastle University Faculty of Medical Sciences Fellowship
- Biotechnology and Biological Sciences Research Council [BB/H022384/1, BB/M023389/1, BB/R008167/1, 1368759, BB/J007803/1, BB/M023311/1, BB/K017314/1] Funding Source: researchfish
- Cancer Research UK [12825] Funding Source: researchfish
- Medical Research Council [G0400074, G0900652, MR/L016354/1, G1100540, G0502157] Funding Source: researchfish
- BBSRC [BB/R008167/1, BB/H022384/1, BB/M023389/1, BB/K017314/1, BB/J007803/1, BB/M023311/1] Funding Source: UKRI
- MRC [MR/L016354/1, G0900652, G0502157, G1100540, G0400074] Funding Source: UKRI
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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.
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