TY - JOUR
T1 - Insights into the GSDMB-mediated cellular lysis and its targeting by IpaH7.8
AU - Yin, Hang
AU - Zheng, Jian
AU - He, Qiuqiu
AU - Zhang, Xuan
AU - Li, Xuzichao
AU - Ma, Yongjian
AU - Liang, Xiao
AU - Gao, Jiaqi
AU - Kocsis, Benjamin L.
AU - Li, Zhuang
AU - Liu, Xiang
AU - Alto, Neal M.
AU - Li, Long
AU - Zhang, Heng
N1 - Funding Information:
We thank the staffs from BL17B/BL18U1/BL19U1/BL19U2/BL01B beamlines of the National Facility for Protein Science in Shanghai (NFPS) at Shanghai Synchrotron Radiation Facility, for assistance during data collection. We thank the staffs, especially Dr. Guangfeng Liu, from BL19U2 beamline of NFPS, for assistance during data collection. We thank Dr. Guimei Yu for critical reading. This work is supported by the National Natural Science Foundation of China Grants (32071218 to H.Z.), the National Key Research and Development Program of China (2018YFC1313002 to L.L.), the National Institute of Health (grant # AI083359 to N.M.A.), the Welch Foundation (grant #I-1704 to N.M.A.), and the Open Project Funding of the State Key Laboratory of Biocatalysis and Enzyme Engineering (SKLBEE2022005 to H.Y.).
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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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U2 - 10.1038/s41467-022-35725-0
DO - 10.1038/s41467-022-35725-0
M3 - Article
C2 - 36599845
AN - SCOPUS:85145512713
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 61
ER -