期刊
NATURE
卷 599, 期 7884, 页码 290-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-021-04020-1
关键词
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资金
- National Key Research and Development Programs of China [2017YFA0505900, 2016YFA0501500]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDB37030202, XDB29020202]
- National Natural Science Foundation of China [81788104, 81922043, 21622501, 21974002]
- Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences [2019-I2M-5-084]
This study identified a novel post-translational modification, ADP riboxanation, mediated by the Shigella effector OspC3, which inactivates the LPS sensing pathway of caspase-4 and caspase-11 and prevents pyroptosis. ADP riboxanation modification on Arg314 and Arg310 in caspase-4 and caspase-11 inhibits their activity, leading to evasion of host defense against Shigella infection. This bacterial virulence mechanism highlights the importance of ADP riboxanation in preventing LPS-induced pyroptosis.
This study reports the identification of a new post-translational modification, termed ADP riboxanation, which is mediated by the Shigella effector OspC3 and inactivates the cytosolic LPS sensing pathway of caspase-4 and caspase-11. Mouse caspase-11 and human caspase-4 and caspase-5 recognize cytosolic lipopolysaccharide (LPS) to induce pyroptosis by cleaving the pore-forming protein GSDMD(1-5). This non-canonical inflammasome defends against Gram-negative bacteria(6,7). 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 thailandensis(8). 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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