USP20 deubiquitinates and stabilizes the reticulophagy receptor RETREG1/FAM134B to drive reticulophagy.

Autophagy Pub Date : 2024-08-01 Epub Date: 2024-05-12 DOI:10.1080/15548627.2024.2347103
Man Zhang, Zhangshun Wang, Qing Zhao, Qian Yang, Jieyun Bai, Cuiwei Yang, Zai-Rong Zhang, Yanfen Liu
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引用次数: 0

Abstract

The endoplasmic reticulum (ER) serves as a hub for various cellular processes, and maintaining ER homeostasis is essential for cell function. Reticulophagy is a selective process that removes impaired ER subdomains through autophagy-mediatedlysosomal degradation. While the involvement of ubiquitination in autophagy regulation is well-established, its role in reticulophagy remains unclear. In this study, we screened deubiquitinating enzymes (DUBs) involved in reticulophagy and identified USP20 (ubiquitin specific peptidase 20) as a key regulator of reticulophagy under starvation conditions. USP20 specifically cleaves K48- and K63-linked ubiquitin chains on the reticulophagy receptor RETREG1/FAM134B (reticulophagy regulator 1), thereby stabilizing the substrate and promoting reticulophagy. Remarkably, despite lacking a transmembrane domain, USP20 is recruited to the ER through its interaction with VAPs (VAMP associated proteins). VAPs facilitate the recruitment of early autophagy proteins, including WIPI2 (WD repeat domain, phosphoinositide interacting 2), to specific ER subdomains, where USP20 and RETREG1 are enriched. The recruitment of WIPI2 and other proteins in this process plays a crucial role in facilitating RETREG1-mediated reticulophagy in response to nutrient deprivation. These findings highlight the critical role of USP20 in maintaining ER homeostasis by deubiquitinating and stabilizing RETREG1 at distinct ER subdomains, where USP20 further recruits VAPs and promotes efficient reticulophagy.Abbreviations: ACTB actin beta; ADRB2 adrenoceptor beta 2; AMFR/gp78 autocrine motility factor receptor; ATG autophagy related; ATL3 atlastin GTPase 3; BafA1 bafilomycin A1; BECN1 beclin 1; CALCOCO1 calcium binding and coiled-coil domain 1; CCPG1 cell cycle progression 1; DAPI 4',6-diamidino-2-phenylindole; DTT dithiothreitol; DUB deubiquitinating enzyme; EBSS Earle's Balanced Salt Solution; FFAT two phenylalanines (FF) in an acidic tract; GABARAP GABA type A receptor-associated protein; GFP green fluorescent protein; HMGCR 3-hydroxy-3-methylglutaryl-CoA reductase; IL1B interleukin 1 beta; LIR LC3-interacting region; MAP1LC3/LC3 microtubule associated protein 1 light chain 3; PIK3C3/Vps34 phosphatidylinositol 3-kinase catalytic subunit type 3; RB1CC1/FIP200 RB1 inducible coiled-coil 1; RETREG1/FAM134B reticulophagy regulator 1; RFP red fluorescent protein; RHD reticulon homology domain; RIPK1 receptor interacting serine/threonine kinase 1; RTN3L reticulon 3 long isoform; SEC61B SEC61 translocon subunit beta; SEC62 SEC62 homolog, preprotein translocation factor; SIM super-resolution structured illumination microscopy; SNAI2 snail family transcriptional repressor 2; SQSTM1/p62 sequestosome 1; STING1/MITA stimulator of interferon response cGAMP interactor 1; STX17 syntaxin 17; TEX264 testis expressed 264, ER-phagy receptor; TNF tumor necrosis factor; UB ubiquitin; ULK1 unc-51 like autophagy activating kinase 1; USP20 ubiquitin specific peptidase 20; USP33 ubiquitin specific peptidase 33; VAMP8 vesicle associated membrane protein 8; VAPs VAMP associated proteins; VMP1 vacuole membrane protein 1; WIPI2 WD repeat domain, phosphoinositide interacting 2; ZFYVE1/DFCP1 zinc finger FYVE-type containing 1.

USP20 去泛素化并稳定网状吞噬受体 RETREG1/FAM134B,以驱动网状吞噬。
内质网(ER)是各种重要细胞过程的枢纽,维持ER的平衡对细胞功能至关重要。网吞噬是一种选择性过程,通过自噬体和溶酶体降解清除受损的ER亚域。泛素化参与自噬调控的作用已得到证实,但其在网状吞噬中的作用仍不清楚。在这项研究中,我们筛选了参与网吞噬的去泛素化酶(DUBs),发现 USP20(泛素特异性肽酶 20)是饥饿条件下网吞噬的关键调节因子。USP20 能特异性地裂解网状吞噬受体 RETREG1/FAM134B(网状吞噬调节因子 1)上与 K48 和 K63 链接的泛素链,从而稳定底物并促进网状吞噬。值得注意的是,尽管 USP20 缺乏跨膜结构域,但它仍能通过与 VAPs(VAMP 相关蛋白)的相互作用被招募到 ER。VAPs 可促进早期自噬蛋白(包括 WIPI2(WD 重复结构域,磷脂酰肌醇相互作用 2))被招募到特定的 ER 亚域,USP20 和 RETREG1 就富集在这些亚域中。WIPI2 和其他蛋白质的这种招募在促进 RETREG1 介导的网状吞噬作用以应对营养匮乏方面起着至关重要的作用。这些发现凸显了 USP20 通过在不同的 ER 亚域去泛素化和稳定 RETREG1 在维持 ER 平衡方面的关键作用,USP20 在 ER 亚域进一步招募 VAPs 并促进有效的网吞噬。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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