WASH inhibits autophagy through suppression of Beclin 1 ubiquitination
WASH inhibits autophagy through suppression of Beclin 1 ubiquitination
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WASH 通过抑制 Beclin 1 泛素化来抑制自噬
DOI：
10.1038/emboj.2013.189
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发表时间：
2013-10-16
期刊：
影响因子：
11.4
通讯作者：
Fan, Zusen
中科院分区：
文献类型：
--
作者：
Xia, Pengyan;Wang, Shuo;Fan, Zusen
自噬降解细胞质蛋白和细胞器以回收细胞存活和组织稳态所需的细胞组分。然而，尚不清楚自噬在哺乳动物细胞中是如何调节的。WASH（Wiskott-Aldrich综合征蛋白（WASP）和SCAR同源物）通过经由Arp 2/3活化促进小管分裂而在内体分选中起重要作用。在这里，我们证明了WASH在调节自噬中的新功能。我们发现WASH缺乏导致小鼠胚胎早期死亡和广泛的自噬。WASH抑制空泡蛋白分选（Vps）34激酶活性和自噬诱导。我们确定WASH是Beclin 1的一个新的相互作用因子。Beclin 1在经历自噬的细胞中通过赖氨酸63连接在赖氨酸437处泛素化。Ambra 1是一种E3连接酶，用于Beclin 1的赖氨酸63连接泛素化，这是饥饿诱导的自噬所必需的。Beclin 1的赖氨酸437泛素化增强了与Vps 34的结合，从而促进了Vps 34的活性。WASH可以抑制Beclin 1泛素化为Beclin Vps 34活性，从而抑制自噬。
Autophagy degrades cytoplasmic proteins and organelles to recycle cellular components that are required for cell survival and tissue homeostasis. However, it is not clear how autophagy is regulated in mammalian cells. WASH (Wiskott-Aldrich syndrome protein (WASP) and SCAR homologue) plays an essential role in endosomal sorting through facilitating tubule fission via Arp2/3 activation. Here, we demonstrate a novel function of WASH in modulation of autophagy. We show that WASH deficiency causes early embryonic lethality and extensive autophagy of mouse embryos. WASH inhibits vacuolar protein sorting (Vps)34 kinase activity and autophagy induction. We identified that WASH is a new interactor of Beclin 1. Beclin 1 is ubiquitinated at lysine 437 through lysine 63 linkage in cells undergoing autophagy. Ambra1 is an E3 ligase for lysine 63-linked ubiquitination of Beclin 1 that is required for starvation-induced autophagy. The lysine 437 ubiquitination of Beclin 1 enhances the association with Vps34 to promote Vps34 activity. WASH can suppress Beclin 1 ubiquitination to inactivate Vps34 activity leading to suppression of autophagy.