SQSTM1/p62 (sequestosome 1) senses cellular ubiquitin stress through E2-mediated ubiquitination
SQSTM1/p62 (sequestosome 1) senses cellular ubiquitin stress through E2-mediated ubiquitination
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SQSTM1/p62 (sequestosome 1) 通过 E2 介导的泛素化感知细胞泛素应激
DOI：
10.1080/15548627.2017.1332566
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发表时间：
2017-11
期刊：
影响因子：
13.3
通讯作者：
Hu Ronggui
中科院分区：
文献类型：
--
作者：
Yang Jiao;Peng Hong;Xu Yumin;Xie Xiaoduo;Hu Ronggui
摘要细胞内泛素（Ub）稳态的改变，即Ub应激，是多种条件下细胞反应的特征和影响，但其潜在机制尚不完全清楚。我们最近报道了巨自噬/自噬受体SQSTM 1/p62，作为一种新的Ub传感器，在Ub+应激时激活自噬（上调Ub水平）。首先，SQSTM 1被发现经历广泛的泛素化，并激活自噬下的Ub+应激诱导的延长硼替佐米（BTZ）处理，Ub过表达或热休克。从机制上讲，SQSTM 1的泛素化破坏了其乌巴结构域的二聚化，将其从自抑制构象转换为识别多聚泛素化货物，促进自噬通量。有趣的是，Ub+应激响应SQSTM 1泛素化是由Ub结合酶UBE 2D 2/3以独特的E2依赖性方式介导的。因此，我们的工作揭示了SQSTM 1如何感知细胞Ub应激条件并调节选择性自噬以应对各种内在或外在挑战的新机制。
ABSTRACT The alterations in cellular ubiquitin (Ub) homeostasis, known as Ub stress, feature and affect cellular responses in multiple conditions, yet the underlying mechanisms are incompletely understood. We recently reported that the macroautophagy/autophagy receptor SQSTM1/p62, functions as a novel Ub sensor to activate autophagy upon Ub+ stress (upregulation of the Ub level). First, SQSTM1 was found to undergo extensive ubiquitination and activate autophagy under Ub+ stress induced by prolonged Bortezomib (BTZ) treatment, Ub overexpression or by heat shock. Mechanistically, Ubiquitination of SQSTM1 disrupts its dimerization of the UBA domain, switching it from an auto-inhibitory conformation to recognize poly-ubiquitinated cargoes, promoting autophagic flux. Interestingly, Ub+ stress-responsive SQSTM1 ubiquitination is mediated by Ub conjugating enzymes, UBE2D2/3, in a unique E2-dependent manner. Our work has thus revealed a novel mechanism for how SQSTM1 senses cellular Ub stress conditions and regulates selective autophagy in response to diverse intrinsic or extrinsic challenges.