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

被引：147

作者：

Carroll, Bernadette ^{[1
]}

Otten, Elsje G. ^{[1
]}

Manni, Diego ^{[1
]}

Stefanatos, Rhoda ^{[1
]}

Menzies, Fiona M. ^{[2
]}

Smith, Graham R. ^{[1
,3
]}

Jurk, Diana ^{[1
]}

Kenneth, Niall ^{[1
]}

Wilkinson, Simon ^{[4
]}

Passos, Joao F. ^{[1
]}

Attems, Johannes ^{[5
]}

Veal, Elizabeth A. ^{[1
]}

Teyssou, Elisa ^{[6
]}

Seilhean, Danielle ^{[6
,7
]}

Millecamps, Stephanie ^{[6
]}

Eskelinen, Eeva-Liisa ^{[8
]}

Bronowska, Agnieszka K. ^{[9
]}

Rubinsztein, David C. ^{[2
,10
]}

Sanz, Alberto ^{[1
]}

Korolchuk, Viktor I. ^{[1
]}

机构：

[1] Newcastle Univ, NUIA, Inst Cell & Mol Biosci ICaMB, Campus Ageing & Vital, Newcastle Upon Tyne NE4 5PL, Tyne & Wear, England

[2] Wellcome Trust Res Labs, Cambridge Inst Med Res, MRC Bldg,Hills Rd, Cambridge CB2 0XY, England

[3] Newcastle Univ, BSU, Fac Med Sci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[4] Univ Edinburgh, Inst Genet & Mol Med, Western Gen Hosp, Edinburgh Canc Res UK Ctr, Edinburgh EH4 2XR, Midlothian, Scotland

[5] Newcastle Univ, IoN, NUIA, Campus Ageing & Vital, Newcastle Upon Tyne NE4 5PL, Tyne & Wear, England

[6] Univ Paris 06, Sorbonne Univ, Hop Pitie Salpetriere,Inst Cerveau & Moelle Epini, INSERM,U1127,CNRS,UMR7225,UMRS1127, Paris, France

[7] Hop La Pitie Salpetriere, AP HP, Dept Neuropathol, Paris, France

[8] Univ Helsinki, Dept Biosci, Helsinki 00790, Finland

[9] Newcastle Univ, Sch Chem, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[10] Univ Cambridge, UK Dementia Res Inst, Hills Rd, Cambridge CB2 0XY, England

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

英国生物技术与生命科学研究理事会;

关键词：

TRANSCRIPTION FACTOR NRF2; SELECTIVE AUTOPHAGY; P62; STRESS; DEGRADATION; DISEASE; IDENTIFICATION; INACTIVATION; MUTATIONS; LONGEVITY;

D O I：

10.1038/s41467-017-02746-z

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页数：11

共 58 条

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