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Cell. 2019 Jul 25;178(3):552-566.e20. doi: 10.1016/j.cell.2019.06.007. Epub 2019 Jul 18.

A Bacterial Effector Reveals the V-ATPase-ATG16L1 Axis that Initiates Xenophagy.

Author information

1
College of Biological Sciences, China Agricultural University, 100094 Beijing, China; National Institute of Biological Sciences, Beijing, 102206 Beijing, China.
2
National Institute of Biological Sciences, Beijing, 102206 Beijing, China.
3
Institute of Analytical Chemistry & Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, 100871 Beijing, China.
4
Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland.
5
National Institute of Biological Sciences, Beijing, 102206 Beijing, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101 Beijing, China.
6
National Institute of Biological Sciences, Beijing, 102206 Beijing, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, 102206 Beijing, China. Electronic address: shaofeng@nibs.ac.cn.

Abstract

Antibacterial autophagy (xenophagy) is an important host defense, but how it is initiated is unclear. Here, we performed a bacterial transposon screen and identified a T3SS effector SopF that potently blocked Salmonella autophagy. SopF was a general xenophagy inhibitor without affecting canonical autophagy. S. Typhimurium ΔsopF resembled S. flexneri ΔvirAΔicsB with the majority of intracellular bacteria targeted by autophagy, permitting a CRISPR screen that identified host V-ATPase as an essential factor. Upon bacteria-caused vacuolar damage, the V-ATPase recruited ATG16L1 onto bacteria-containing vacuole, which was blocked by SopF. Mammalian ATG16L1 bears a WD40 domain required for interacting with the V-ATPase. Inhibiting autophagy by SopF promoted S. Typhimurium proliferation in vivo. SopF targeted Gln124 of ATP6V0C in the V-ATPase for ADP-ribosylation. Mutation of Gln124 also blocked xenophagy, but not canonical autophagy. Thus, the discovery of SopF reveals the V-ATPase-ATG16L1 axis that critically mediates autophagic recognition of intracellular pathogen.

KEYWORDS:

ADP-ribosylation; V-ATPase; autophagy; bacteria-host interaction; innate immunity; type III secretion system; xenophagy

PMID:
31327526
DOI:
10.1016/j.cell.2019.06.007

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