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. Schmid, Guanghua Xiao, Paul A. Gleeson, Nicholas T. Ktistakis, Peter J. Cullen, Ramnik J. Xavier () and Beth Levine
Additional contact information
Xiaonan Dong: University of Texas Southwestern Medical Center
Yuting Yang: University of Texas Southwestern Medical Center
Zhongju Zou: University of Texas Southwestern Medical Center
Yuting Zhao: University of Texas Southwestern Medical Center
Bo Ci: University of Texas Southwestern Medical Center
Lin Zhong: University of Texas Southwestern Medical Center
Madhura Bhave: University of Texas Southwestern Medical Center
Liwei Wang: University of Texas Southwestern Medical Center
Yi-Chun Kuo: University of Texas Southwestern Medical Center
Xiao Zang: University of Texas Southwestern Medical Center
Rui Zhong: University of Texas Southwestern Medical Center
Elizabeth R. Aguilera: University of Texas Southwestern Medical Center
R. Blake Richardson: University of Texas Southwestern Medical Center
Boris Simonetti: University of Bristol
John W. Schoggins: University of Texas Southwestern Medical Center
Julie K. Pfeiffer: University of Texas Southwestern Medical Center
Li Yu: Tsinghua University
Xuewu Zhang: University of Texas Southwestern Medical Center
Yang Xie: University of Texas Southwestern Medical Center
Sandra L. Schmid: University of Texas Southwestern Medical Center
Guanghua Xiao: University of Texas Southwestern Medical Center
Paul A. Gleeson: The University of Melbourne
Nicholas T. Ktistakis: Signalling Programme, The Babraham Institute
Peter J. Cullen: University of Bristol
Ramnik J. Xavier: Harvard School of Medicine
Beth Levine: University of Texas Southwestern Medical Center

Nature, 2021, vol. 589, issue 7842, 456-461

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-020-03056-z

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