Sorting nexin 5 mediates virus-induced autophagy and immunity

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 SchmidGuanghua Xiao, Paul A. Gleeson, Nicholas T. Ktistakis, Peter J. Cullen, Ramnik J. Xavier, Beth Levine

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)456-461
Number of pages6
JournalNature
Volume589
Issue number7842
DOIs
StatePublished - Jan 21 2021

ASJC Scopus subject areas

  • General

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