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研究揭示ER自噬机制
作者:小柯机器人 发布时间:2020/3/12 15:15:18

美国加州大学Jacob E. Corn小组在研究中取得进展。他们发现全基因组的内质网(ER)自噬筛选突出了线粒体代谢和ER驻留泛素样的后转录修饰(UFMylation)的关键作用。相关论文于2020310日发表于国际学术期刊《细胞》杂志上。

通过使用ER-自噬报告系统和全基因组CRISPR干扰(CRISPRi)筛选,他们鉴定了200个高可信度的人类ER-自噬因子。出乎意料的是,ER自噬需要两个途径。首先,线粒体代谢降低会抑制ER自噬,这与一般自噬相反,并且独立于AMPK。其次,ER自噬需要通过ER定位的UFMylation来抑制通过IRE1α的未折叠蛋白质反应。DDRGK1UFL1连接酶带到ER表面,到达UFMylate RPN1RPL26,并优先靶向ER片层进行降解,类似于线粒体自噬过程中的PINK1-Parkin调节。

他们的数据提供了对内质网自噬的细胞逻辑的洞察力,揭示了细胞器自噬之间的相似性,并为相对未知的内质网降解过程提供了切入点。

据悉,细胞器的选择性自噬对于细胞分化、体内平衡和机体健康至关重要。ER的自噬(ER自噬)与人类神经病有关,但除少数自噬体受体和重塑子外,人们对其了解甚少。

附:英文原文

Title: A Genome-wide ER-phagy Screen Highlights Key Roles of Mitochondrial Metabolism and ER-Resident UFMylation

Author: Jin Rui Liang, Emily Lingeman, Thao Luong, Saba Ahmed, Matthias Muhar, Truc Nguyen, James A. Olzmann, Jacob E. Corn

Issue&Volume: 2020-03-10

Abstract: Selective autophagy of organelles is critical for cellular differentiation, homeostasis,and organismal health. Autophagy of the ER (ER-phagy) is implicated in human neuropathybut is poorly understood beyond a few autophagosomal receptors and remodelers. Byusing an ER-phagy reporter and genome-wide CRISPRi screening, we identified 200 high-confidencehuman ER-phagy factors. Two pathways were unexpectedly required for ER-phagy. First,reduced mitochondrial metabolism represses ER-phagy, which is opposite of generalautophagy and is independent of AMPK. Second, ER-localized UFMylation is requiredfor ER-phagy to repress the unfolded protein response via IRE1α. The UFL1 ligase isbrought to the ER surface by DDRGK1 to UFMylate RPN1 and RPL26 and preferentiallytargets ER sheets for degradation, analogous to PINK1-Parkin regulation during mitophagy.Our data provide insight into the cellular logic of ER-phagy, reveal parallels betweenorganelle autophagies, and provide an entry point to the relatively unexplored processof degrading the ER network.

DOI: 10.1016/j.cell.2020.02.017

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30161-6

期刊信息
Cell:《细胞》,创刊于1974年。隶属于细胞出版社,最新IF:36.216
官方网址:https://www.cell.com/