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

Cell Death & Differentiation volume 30, pages 2120–2134 (2023)Cite this article

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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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Fig. 1: GSDMB is cleaved during apoptosis.
Fig. 2: Apoptosis inhibits non-canonical pyroptosis.
Fig. 3: Apoptotic inhibition of non-canonical pyroptosis is dependent on caspase-7.
Fig. 4: Caspase-7-mediated GSDMB cleavage is necessary for the apoptotic inhibition of non-canonical pyroptosis.
Fig. 5: GSDMB cleaved at D91 site cannot promote the enzyme activity of caspase-4.
Fig. 6: GSDMB C-terminus (92-417 aa) can bind to GSDMB N-terminus (1-91 aa) to block its function.
Fig. 7: Apoptotic inhibition of non-canonical pyroptosis is a self-protective pathway during bacterial infection.
Fig. 8: Conclusion.

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Data availability

The data sets used in the current study are available from the corresponding author upon reasonable request. The western blot data are provided in Supplementary Materials (Original western blots).

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Acknowledgements

We appreciated the carefully check of language by Dr. Chen, Jiong from Nanjing University. We also thank Prof. Shu Zhu from University of Science and Technology of China for providing the Caspase11-KO mice.

Funding

This work was supported by grants from the Ministry of Science and Technology of China (grant 2018YFA0801100 and 2021YFF0702100), the National Natural Science Foundation of China (grant 31971056, 31772550, 32000513), the Natural Science Foundation of Jiangsu Province (BK20181260), the Fundamental Research Funds for the Central Universities (14380516 and 021414380533).

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  1. These authors contributed equally: Xu Li, Tianxun Zhang.

Authors and 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

    Xu Li, Tianxun Zhang, Lulu Kang, Ruyue Xin, Minli Sun, Qianyue Chen, Jingwen Pei, Xiang Gao & Zhaoyu Lin

  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

    Xu Li

  3. Department of Oral Surgery, Shanghai Jiao Tong University, 639 Zhizaoju Road, Huangpu District, Shanghai, CN, 200240, China

    Qin Chen

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Contributions

ZL and XG supervised the whole project. XL conceived, designed and performed experiments. XL, ZL, and XG analyzed the experiments and wrote the manuscript. TZ participated in the induction of necroptosis and Live-cell imaging experiments. RX and Qin Chen performed genotype identification of mice used in this project. LK, TZ, RX, Qianyue Chen and JP participated in the construction of septic mouse model. MS participated in the FACS experiments.

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Correspondence to Xiang Gao or Zhaoyu Lin.

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All mice were housed in a specific pathogen-free facility accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International. All animal welfare and experimental procedures were approved by the Animal Care and Use Committee of the Model Animal Research Center, Nanjing University (Nanjing, China).

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Li, X., Zhang, T., Kang, L. et al. Apoptotic caspase-7 activation inhibits non-canonical pyroptosis by GSDMB cleavage. Cell Death Differ 30, 2120–2134 (2023). https://doi.org/10.1038/s41418-023-01211-3

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