Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
EMBO J. 2013 Oct 16;32(20):2685-96. doi: 10.1038/emboj.2013.189. Epub 2013 Aug 23.
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.
自噬降解细胞质蛋白和细胞器，以回收细胞存活和组织平衡所需的细胞成分。然而，目前尚不清楚哺乳动物细胞中的自噬是如何被调节的。WASH（Wiskott-Aldrich 综合征蛋白（WASP）和 SCAR 同源物）通过激活 Arp2/3 促进小管裂变，在内涵体分选过程中发挥着重要作用。在这里，我们证明了 WASH 在调节自噬方面的一个新功能。我们发现 WASH 缺乏会导致早期胚胎致死和小鼠胚胎广泛的自噬。WASH 抑制液泡蛋白分选（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蛋白。在经历自噬的细胞中，Beclin 1 在赖氨酸 437 处通过赖氨酸 63 连接被泛素化。Ambra1 是 Beclin 1 赖氨酸 63 连接泛素化的 E3 连接酶，对于饥饿诱导的自噬是必需的。Beclin 1 的赖氨酸 437 泛素化增强了与 Vps34 的结合，从而促进了 Vps34 的活性。WASH 可以抑制 Beclin 1 的泛素化，从而使 Vps34 失活，导致自噬抑制。
