2. Academic Validation
  3. Insights into the GSDMB-mediated cellular lysis and its targeting by IpaH7.8

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

  • Nat Commun. 2023 Jan 4;14(1):61. doi: 10.1038/s41467-022-35725-0.
Hang Yin # 1 2,  Jian Zheng # 1 3,  Qiuqiu He # 1 4,  Xuan Zhang 3,  Xuzichao Li 4,  Yongjian Ma 4,  Xiao Liang 4,  Jiaqi Gao 4,  Benjamin L Kocsis 5,  Zhuang Li 2,  Xiang Liu 6,  Neal M Alto 5,  Long Li 7 8,  Heng Zhang 9 10
Affiliations

Affiliations

  • 1 The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Haihe Laboratory of Cell Ecosystem, Tianjin Institute of Immunology, Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China.
  • 2 State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, 430062, Wuhan, China.
  • 3 Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China.
  • 4 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China.
  • 5 Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • 6 State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, 300071, Tianjin, China.
  • 7 The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Haihe Laboratory of Cell Ecosystem, Tianjin Institute of Immunology, Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China. [email protected].
  • 8 Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China. [email protected].
  • 9 The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Haihe Laboratory of Cell Ecosystem, Tianjin Institute of Immunology, Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China. [email protected].
  • 10 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China. [email protected].
  • # Contributed equally.
PMID: 36599845 DOI: 10.1038/s41467-022-35725-0
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.

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