Institute for Cell and Molecular Biosciences (ICaMB), Newcastle University Institute for Ageing (NUIA), Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL, UK.
Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge, CB2 0XY, UK.
Nat Commun. 2018 Jan 17;9(1):256. doi: 10.1038/s41467-017-02746-z.
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.
细胞内稳态途径，如巨自噬（以下简称自噬），受到基本机制的调控，这些基本机制在整个真核生物界中都是保守的。然而，这些机制在高等生物中是如何进一步进化的，目前还知之甚少。在这里，我们描述了脊椎动物中自噬途径的一种修饰，它可以促进其在氧化应激下的活性。我们已经在一个典型的自噬受体 SQSTM1/p62 中鉴定出两个对氧化敏感的半胱氨酸残基，这允许在应激条件下激活促进生存的自噬。果蝇 p62 同源物 Ref(2)P 缺乏这些对氧化敏感的半胱氨酸残基，而将其引入蛋白中会增加蛋白周转率并提高果蝇的应激抗性，而人类 p62 氧化的干扰可能导致与年龄相关的病理学。我们提出，p62 的氧化还原敏感性可能是在脊椎动物中进化而来的，作为一种机制，可以在氧化应激下激活自噬，以维持细胞内稳态并提高细胞存活率。
