2. Academic Validation
  3. Shigella evades pyroptosis by arginine ADP-riboxanation of caspase-11

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

  • Nature. 2021 Nov;599(7884):290-295. doi: 10.1038/s41586-021-04020-1.
Zilin Li 1 2,  Wang Liu 1 2,  Jiaqi Fu 3,  Sen Cheng 2 3,  Yue Xu 1 2,  Zhiqiang Wang 2,  Xiaofan Liu 2,  Xuyan Shi 2,  Yaxin Liu 2,  Xiangbing Qi 2,  Xiaoyun Liu 4 5,  Jingjin Ding 2 6,  Feng Shao 7 8 9 10
Affiliations

Affiliations

  • 1 Research Unit of Pyroptosis and Immunity, Chinese Academy of Medical Sciences and National Institute of Biological Sciences, Beijing, China.
  • 2 National Institute of Biological Sciences, Beijing, China.
  • 3 Institute of Analytical Chemistry & Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
  • 4 Institute of Analytical Chemistry & Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing, China. [email protected].
  • 5 Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. [email protected].
  • 6 National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 7 Research Unit of Pyroptosis and Immunity, Chinese Academy of Medical Sciences and National Institute of Biological Sciences, Beijing, China. [email protected].
  • 8 National Institute of Biological Sciences, Beijing, China. [email protected].
  • 9 National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. [email protected].
  • 10 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China. [email protected].
PMID: 34671164 DOI: 10.1038/s41586-021-04020-1
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.

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