GSDMEa-mediated pyroptosis is bi-directionally regulated by caspase and required for effective bacterial clearance in teleost

• Published in: Cell Death & Disease
• Main Authors: Xu, Hang, Jiang, Shuai, Yu, Chao, Yuan, Zihao, Sun, Li
• Format: Report
• Language: English
• Published: SPRINGERNATURE 2022
• Subjects: Cell Biology; VIBRIO-HARVEYI; CELL-DEATH; NLRP3 INFLAMMASOME; GASDERMIN D; CLEAVAGE; INDUCTION; INFECTION; APOPTOSIS; CHOLERAE; Scophthalmus maximus; Turbot
• Online Access: http://ir.qdio.ac.cn/handle/337002/179388; https://doi.org/10.1038/s41419-022-04896-5

Gasdermin (GSDM) is a family of pore-forming proteins that, after cleavage by caspase (CASP), induce a type of programmed necrotic cell death called pyroptosis. Gasdermin E (GSDME) is the only pyroptosis-inducing member of the GSDM family existing in teleost. To date, the regulation and function of teleost GSDME in response to bacterial infection remain elusive. In this study, we observed activation of GSDME, as well as multiple CASPs, in turbot Scophthalmus maximus during the infection of the bacterial pathogen Vibrio harveyi. Turbot has two GSDME orthologs named SmGSDMEa and SmGSDMEb. We found that SmGSDMEa was specifically cleaved by turbot CASP (SmCASP) 3/7 and SmCASP6, which produced two different N-terminal (NT) fragments. Only the NT fragment produced by SmCASP3/7 cleavage was able to induce pyroptosis. Ectopically expressed SmCASP3/7 activated SmGSDMEa, resulting in pyroptotic cell death. In contrast, SmCASP6 inactivated SmGSDMEa by destructive cleavage of the NT domain, thus nullifying the activation effect of SmCASP3/7. Unlike SmGSDMEa, SmGSDMEb was cleaved by SmCASP8 and unable to induce cell death. V. harveyi infection dramatically promoted the production and activation of SmGSDMEa, but not SmGSDMEb, and caused pyroptosis in turbot. Interference with SmCASP3/7 activity significantly enhanced the invasiveness and lethality of V. harveyi in a turbot infection model. Together, these results revealed a previously unrecognized bi-directional regulation mode of GSDME-mediated pyroptosis, and a functional difference between teleost GSDMEa and GSDMEb in the immune defense against bacterial infection.