2. Academic Validation
  3. Apoptotic caspase-7 activation inhibits non-canonical pyroptosis by GSDMB cleavage

Apoptotic caspase-7 activation inhibits non-canonical pyroptosis by GSDMB cleavage

  • Cell Death Differ. 2023 Aug 17. doi: 10.1038/s41418-023-01211-3.
Xu Li # 1 2,  Tianxun Zhang # 1,  Lulu Kang 1,  Ruyue Xin 1,  Minli Sun 1,  Qianyue Chen 1,  Jingwen Pei 1,  Qin Chen 3,  Xiang Gao 4,  Zhaoyu Lin 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animals for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, 210061, China.
  • 2 Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
  • 3 Department of Oral Surgery, Shanghai Jiao Tong University, 639 Zhizaoju Road, Huangpu District, Shanghai, CN, 200240, China.
  • 4 State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animals for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, 210061, China. [email protected].
  • 5 State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animals for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, 210061, China. [email protected].
  • # Contributed equally.
PMID: 37591921 DOI: 10.1038/s41418-023-01211-3
Abstract

GSDMB is associated with several inflammatory diseases, such as asthma, sepsis and colitis. GZMA is released by cytotoxic lymphocytes and cleaves GSDMB at the K244 site and to induce GSDMB N-terminus dependent Pyroptosis. This cleavage of GSDMB is noncell autonomous. In this study, we demonstrated that the GSDMB-N domain (1-91 aa) was important for a novel cell-autonomous function and that GSDMB could bind caspase-4 and promote noncanonical Pyroptosis. Furthermore, activated caspase-7 cleaved GSDMB at the D91 site to block GSDMB-mediated promotion of noncanonical Pyroptosis during Apoptosis. Mechanistically, the cleaved GSDMB-C-terminus (92-417 aa) binds to the GSDMB-N-terminus (1-91 aa) to block the function of GSDMB. During E. coli and S. Typhimurium Infection, inhibition of the caspase-7/GSDMB axis resulted in more pyroptotic cells. Furthermore, in a septic mouse model, caspase-7 inhibition or deficiency in GSDMB-transgenic mice led to more severe disease phenotypes. Overall, we demonstrate that apoptotic caspase-7 activation inhibits non-canonical Pyroptosis by cleaving GSDMB and provide new targets for sepsis therapy.

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