小柯机器人

美国哈佛医学院马萨诸塞州总医院Ramnik J. Xavier课题组的最新研究表明，Sorting nexin 5介导了病毒诱导的自噬和免疫。该研究成果于2020年12月16日在线发表在国际学术期刊《自然》上。

使用针对全基因组的小干扰RNA筛选，研究人员发现内吞体蛋白sorting nexin 5（SNX5）对于病毒诱导的自噬是必需的，但对于基体、应激或内体诱导的自噬则非必需。研究表明，在体外敲除SNX5增加了细胞对病毒感染的敏感性，并且在几种人类病毒感染的小鼠模型中，敲除Snx5增加了小鼠的致死率。

从机制上讲，SNX5与Beclin 1和含III类磷脂酰肌醇3-激酶（PI3KC3）复合物1（PI3KC3-C1）的ATG14相互作用，增加了纯化PI3KC3-C1的脂质激酶活性，SNX5是内吞体产生磷脂酰肌醇3-磷酸盐（PtdIns（3）P）和招募PtdIns（3）P结合蛋白WIPI到含病毒内吞体所必需的。这些发现揭示了一种在病毒感染期间环境和细胞器特定的自噬开启机制，其依赖于内吞体中SNX5调控的PI3KC3-C1激活。

据了解，自噬是一种通过溶酶体途径发生降解的过程，在免疫功能的多个方面发挥重要作用，包括免疫系统发育、调节先天性和适应性免疫、炎症反应、细胞内微生物的选择性降解以及保护宿主免受传染病的危害。已知自噬是由诸如营养匮乏和mTOR抑制之类的刺激引起，但对于哺乳动物细胞如何响应病毒感染而启动自噬体生物发生的过程了解甚少。

附：英文原文

Title: Sorting nexin 5 mediates virus-induced autophagy and immunity

Author: Xiaonan Dong, Yuting Yang, Zhongju Zou, Yuting Zhao, Bo Ci, Lin Zhong, Madhura Bhave, Liwei Wang, Yi-Chun Kuo, Xiao Zang, Rui Zhong, Elizabeth R. Aguilera, R. Blake Richardson, Boris Simonetti, John W. Schoggins, Julie K. Pfeiffer, Li Yu, Xuewu Zhang, Yang Xie, Sandra L. Schmid, Guanghua Xiao, Paul A. Gleeson, Nicholas T. Ktistakis, Peter J. Cullen, Ramnik J. Xavier, Beth Levine

Issue&Volume: 2020-12-16

Abstract: Autophagy, a process of degradation that occurs via the lysosomal pathway, has an essential role in multiple aspects of immunity, including immune system development, regulation of innate and adaptive immune and inflammatory responses, selective degradation of intracellular microorganisms, and host protection against infectious diseases1,2. Autophagy is known to be induced by stimuli such as nutrient deprivation and suppression of mTOR, but little is known about how autophagosomal biogenesis is initiated in mammalian cells in response to viral infection. Here, using genome-wide short interfering RNA screens, we find that the endosomal protein sorting nexin 5 (SNX5)3,4 is essential for virus-induced, but not for basal, stress- or endosome-induced, autophagy. We show that SNX5 deletion increases cellular susceptibility to viral infection in vitro, and that Snx5 knockout in mice enhances lethality after infection with several human viruses. Mechanistically, SNX5 interacts with beclin 1 and ATG14-containing class III phosphatidylinositol-3-kinase (PI3KC3) complex 1 (PI3KC3-C1), increases the lipid kinase activity of purified PI3KC3-C1, and is required for endosomal generation of phosphatidylinositol-3-phosphate (PtdIns(3)P) and recruitment of the PtdIns(3)P-binding protein WIPI2 to virion-containing endosomes. These findings identify a context- and organelle-specific mechanism—SNX5-dependent PI3KC3-C1 activation at endosomes—for initiation of autophagy during viral infection. Genome-wide siRNA screens identify an essential function for sorting nexin 5 in virus-induced autophagy and immunity mediated via class III phosphatidylinositol-3-kinase complex 1.

DOI: 10.1038/s41586-020-03056-z

Source: https://www.nature.com/articles/s41586-020-03056-z

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