【Cell】V-ATPase-ATG16L1 Axis Initiates Xenophagy

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A Bacterial Effector Reveals the V-ATPase-ATG16L1 Axis that Initiates Xenophagy
Yue Xu Ping Zhou Sen Cheng Qiuhe Lu Kathrin Nowak Ann-Katrin Hopp Lin Li Xuyan Shi Zhiwei Zhou Wenqing Gao Da Li Huabin He Xiaoyun Liu Jingjin Ding Michael O. Hottiger Feng Shao  

Highlights

• [size=1.25]•Transposon screen in Salmonella identifies SopF, a xenophagy-specific inhibitor
  
• [size=1.25]•CRISPR screen identifies the V-ATPase-ATG16L1 axis that initiates xenophagy
  
• [size=1.25]•SopF disrupts infection-induced V-ATPase-ATG16L1 association to promote replication
  
• [size=1.25]•SopF ADP-ribosylates Gln124 of ATP6V0C in the V-ATPase to block bacterial autophagy
  
  

SummaryAntibacterial 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 Δ sopF resembled S. flexneri ΔvirAΔ icsB 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.