Shigella evades pyroptosis by arginine ADP-riboxanation of caspase-11

Zilin Li, Wang Liu, Jiaqi Fu, Sen Cheng, Yue Xu, Zhiqiang Wang, Xiaofan Liu, Xuyan Shi, Yaxin Liu, Xiangbing Qi, Xiaoyun Liu (), Jingjin Ding and Feng Shao ()
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Zilin Li: Chinese Academy of Medical Sciences and National Institute of Biological Sciences
Wang Liu: Chinese Academy of Medical Sciences and National Institute of Biological Sciences
Jiaqi Fu: Peking University
Sen Cheng: National Institute of Biological Sciences
Yue Xu: Chinese Academy of Medical Sciences and National Institute of Biological Sciences
Zhiqiang Wang: National Institute of Biological Sciences
Xiaofan Liu: National Institute of Biological Sciences
Xuyan Shi: National Institute of Biological Sciences
Yaxin Liu: National Institute of Biological Sciences
Xiangbing Qi: National Institute of Biological Sciences
Xiaoyun Liu: Peking University
Jingjin Ding: National Institute of Biological Sciences
Feng Shao: Chinese Academy of Medical Sciences and National Institute of Biological Sciences

Nature, 2021, vol. 599, issue 7884, 290-295

Abstract: Abstract Mouse caspase-11 and human caspase-4 and caspase-5 recognize cytosolic lipopolysaccharide (LPS) to induce pyroptosis by cleaving the pore-forming protein GSDMD1–5. This non-canonical inflammasome defends against Gram-negative bacteria6,7. Shigella flexneri, which causes bacillary dysentery, lives freely within the host cytosol where these caspases reside. However, the role of caspase-11-mediated pyroptosis in S. flexneri infection is unknown. Here we show that caspase-11 did not protect mice from S. flexneri infection, in contrast to infection with another cytosolic bacterium, Burkholderia thailandensis8. S. flexneri evaded pyroptosis mediated by caspase-11 or caspase 4 (hereafter referred to as caspase-11/4) using a type III secretion system (T3SS) effector, OspC3. OspC3, but not its paralogues OspC1 and 2, covalently modified caspase-11/4; although it used the NAD+ donor, this modification was not ADP-ribosylation. Biochemical dissections uncovered an ADP-riboxanation modification on Arg314 and Arg310 in caspase-4 and caspase-11, respectively. The enzymatic activity was shared by OspC1 and 2, whose ankyrin-repeat domains, unlike that of OspC3, could not recognize caspase-11/4. ADP-riboxanation of the arginine blocked autoprocessing of caspase-4/11 as well as their recognition and cleavage of GSDMD. ADP-riboxanation of caspase-11 paralysed pyroptosis-mediated defence in Shigella-infected mice and mutation of ospC3 stimulated caspase-11- and GSDMD-dependent anti-Shigella humoral immunity, generating a vaccine-like protective effect. Our study establishes ADP-riboxanation of arginine as a bacterial virulence mechanism that prevents LPS-induced pyroptosis.

Date: 2021
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DOI: 10.1038/s41586-021-04020-1

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