Insights into the GSDMB-mediated cellular lysis and its targeting by IpaH7.8

Hang Yin, Jian Zheng, Qiuqiu He, Xuan Zhang, Xuzichao Li, Yongjian Ma, Xiao Liang, Jiaqi Gao, Benjamin L. Kocsis, Zhuang Li, Xiang Liu, Neal M. Alto, Long Li () and Heng Zhang ()
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Hang Yin: Tianjin Medical University
Jian Zheng: Tianjin Medical University
Qiuqiu He: Tianjin Medical University
Xuan Zhang: Tianjin Medical University
Xuzichao Li: Tianjin Medical University
Yongjian Ma: Tianjin Medical University
Xiao Liang: Tianjin Medical University
Jiaqi Gao: Tianjin Medical University
Benjamin L. Kocsis: University of Texas Southwestern Medical Center
Zhuang Li: Hubei University
Xiang Liu: Nankai University
Neal M. Alto: University of Texas Southwestern Medical Center
Long Li: Tianjin Medical University
Heng Zhang: Tianjin Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract The multifunctional GSDMB protein is an important molecule in human immunity. The pyroptotic and bactericidal activity of GSDMB is a host response to infection by the bacterial pathogen Shigella flexneri, which employs the virulence effector IpaH7.8 to ubiquitinate and target GSDMB for proteasome-dependent degradation. Furthermore, IpaH7.8 selectively targets human but not mouse GSDMD, suggesting a non-canonical mechanism of substrate selection. Here, we report the crystal structure of GSDMB in complex with IpaH7.8. Together with biochemical and functional studies, we identify the potential membrane engagement sites of GSDMB, revealing general and unique features of gasdermin proteins in membrane recognition. We further illuminate how IpaH7.8 interacts with GSDMB, and delineate the mechanism by which IpaH7.8 ubiquitinates and suppresses GSDMB. Notably, guided by our structural model, we demonstrate that two residues in the α1-α2 loop make the mouse GSDMD invulnerable to IpaH7.8-mediated degradation. These findings provide insights into the versatile functions of GSDMB, which could open new avenues for therapeutic interventions for diseases, including cancers and bacterial infections.

Date: 2023
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DOI: 10.1038/s41467-022-35725-0

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