小柯机器人

北京生命科学研究所邵峰、北京大学刘小云等研究人员合作发现，志贺氏菌通过caspase-11的精氨酸ADP-riboxanation来逃避焦亡。2021年10月20日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员表示，小鼠的caspase-11和人类的caspase-4和caspase-5识别细胞膜脂多糖（LPS），通过切割成孔蛋白GSDMD来诱导焦亡。这种非经典的炎症体能抵御革兰氏阴性细菌。导致细菌性痢疾的福氏志贺氏菌自由地生活在宿主的细胞膜内，这些caspase就驻扎在那里。然而，caspase-11介导的焦亡在福氏志贺氏菌感染中的作用尚不清楚。

研究人员发现，caspase-11不能保护小鼠免受福氏志贺氏菌感染，这与另一种细胞型细菌Burkholderia thailandensis的感染相反。福氏志贺氏菌利用III型分泌系统（T3SS）效应蛋白OspC3逃避了由caspase-11或caspase 4（以下简称caspase-11/4）介导的焦亡。OspC3，但不是其类似物OspC1和2，共价修饰caspase-11/4；尽管它使用了NAD⁺供体，但这种修饰不是ADP-核糖基化。

生物化学分析发现，在caspase-4和caspase-11中的Arg314和Arg310分别有ADP-riboxanation修饰。OspC1和2也有这种酶活性，它们的蛋白重复域与OspC3不同，不能识别caspase-11/4。精氨酸的ADP-riboxanation阻断了caspase-4/11的自加工，以及它们对GSDMD的识别和切割。caspase-11的ADP-riboxanation破坏了志贺氏菌感染小鼠中焦亡介导的防御，OspC3的突变刺激了caspase-11和GSDMD依赖的抗志贺氏菌体液免疫，产生了类似疫苗的保护效果。这项研究表明，精氨酸的ADP-riboxanation是一种细菌毒力机制，可以防止LPS诱导的焦亡。

附：英文原文

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

Author: Li, Zilin, Liu, Wang, Fu, Jiaqi, Cheng, Sen, Xu, Yue, Wang, Zhiqiang, Liu, Xiaofan, Shi, Xuyan, Liu, Yaxin, Qi, Xiangbing, Liu, Xiaoyun, Ding, Jingjin, Shao, Feng

Issue&Volume: 2021-10-20

Abstract: Mouse caspase-11 and human caspase-4 and caspase-5 recognize cytosolic lipopolysaccharide (LPS) to induce pyroptosis by cleaving the pore-forming protein GSDMD1,2,3,4,5. 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.

DOI: 10.1038/s41586-021-04020-1

Source: https://www.nature.com/articles/s41586-021-04020-1

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