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A bacterial effector reveals the V-ATPase-ATG16L1 axis that initiates xenophagy


Xu, Yue; Zhou, Ping; Cheng, Sen; Lu, Qiuhe; Nowak, Kathrin; Hopp, Ann-Katrin; Li, Lin; Shi, Xuyan; Zhou, Zhiwei; Gao, Wenqing; Li, Da; He, Huabin; Liu, Xiaoyun; Ding, Jingjin; Hottiger, Michael O; Shao, Feng (2019). A bacterial effector reveals the V-ATPase-ATG16L1 axis that initiates xenophagy. Cell, 178(3):552-566.e20.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Department of Molecular Mechanisms of Disease
07 Faculty of Science > Department of Molecular Mechanisms of Disease
Dewey Decimal Classification:570 Life sciences; biology
Scopus Subject Areas:Life Sciences > General Biochemistry, Genetics and Molecular Biology
Uncontrolled Keywords:General Biochemistry, Genetics and Molecular Biology, ADP-ribosylation; V-ATPase; autophagy; bacteria-host interaction; innate immunity; type III secretion system; xenophagy
Language:English
Date:1 July 2019
Deposited On:27 Aug 2019 10:45
Last Modified:29 Jul 2020 11:10
Publisher:Cell Press (Elsevier)
ISSN:0092-8674
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.cell.2019.06.007
PubMed ID:31327526
Project Information:
  • : FunderSNSF
  • : Grant ID31003A_176177
  • : Project TitleUncovering the function of cell stress-associated ADP-ribosylomes

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