The ubiquitin-specific protease USP8 directly deubiquitinates SQSTM1/p62 to suppress its autophagic activity
The ubiquitin-specific protease USP8 directly deubiquitinates SQSTM1/p62 to suppress its autophagic activity
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DOI：
10.1080/15548627.2019.1635381
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发表时间：
2019-07-01
期刊：
影响因子：
13.3
通讯作者：
Huang, Chuanxin
中科院分区：
文献类型：
--
作者：
Peng, Hong;Yang, Fang;Huang, Chuanxin
SQSTM1/p62 （sequestosome 1）是一种关键的巨噬/自噬受体，可促进泛素化聚集体的形成和降解。SQSTM1可被泛素化修饰，这种修饰可调节其自噬活性。然而，支持其可逆去泛素化的分子机制从未被描述过。在这里，我们报道了USP8（泛素特异性肽酶8）直接与SQSTM1相互作用并去泛素化。USP8优先去除SQSTM1中赖氨酸11 （K11）连接的泛素链。此外，USP8主要在泛素关联（UBA）结构域的K420位点使SQSTM1去泛素化。最后，在野生型SQSTM1细胞中，USP8抑制了SQSTM1的降解和自噬内流，而用精氨酸替代K420后，USP8对其突变体不起作用。综上所述，USP8通过在K420位点去泛素化SQSTM1，作为自噬的负调节因子。
SQSTM1/p62 (sequestosome 1) is a critical macroautophagy/autophagy receptor that promotes the formation and degradation of ubiquitinated aggregates. SQSTM1 can be modified by ubiquitination, and this modification modulates its autophagic activity. However, the molecular mechanisms underpinning its reversible deubiquitination have never been described. Here we report that USP8 (ubiquitin specific peptidase 8) directly interacted with and deubiquitinated SQSTM1. USP8 preferentially removed the lysine 11 (K11)-linked ubiquitin chains from SQSTM1. Moreover, USP8 deubiquitinated SQSTM1 principally at K420 within its ubiquitin-association (UBA) domain. Finally, USP8 inhibited SQSTM1 degradation and autophagic influx in cells with wild-type SQSTM1, but not its mutant with substitution of K420 with an arginine. Taken together, USP8 acts as a negative regulator of autophagy by deubiquitinating SQSTM1 at K420.