Structural mechanisms for regulation of GSDMB pore-forming activity

Xiu Zhong, Huan Zeng, Zhiwei Zhou, Ya Su, Hang Cheng, Yanjie Hou, Yang She, Na Feng, Jia Wang, Feng Shao () and Jingjin Ding ()
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Xiu Zhong: Tsinghua University
Huan Zeng: National Institute of Biological Sciences
Zhiwei Zhou: National Institute of Biological Sciences
Ya Su: National Institute of Biological Sciences
Hang Cheng: Shuimu BioSciences
Yanjie Hou: National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
Yang She: National Institute of Biological Sciences
Na Feng: National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
Jia Wang: National Institute of Biological Sciences
Feng Shao: Tsinghua University
Jingjin Ding: National Institute of Biological Sciences

Nature, 2023, vol. 616, issue 7957, 598-605

Abstract: Abstract Cytotoxic lymphocyte-derived granzyme A (GZMA) cleaves GSDMB, a gasdermin-family pore-forming protein1,2, to trigger target cell pyroptosis3. GSDMB and the charter gasdermin family member GSDMD4,5 have been inconsistently reported to be degraded by the Shigella flexneri ubiquitin-ligase virulence factor IpaH7.8 (refs. 6,7). Whether and how IpaH7.8 targets both gasdermins is undefined, and the pyroptosis function of GSDMB has even been questioned recently6,8. Here we report the crystal structure of the IpaH7.8–GSDMB complex, which shows how IpaH7.8 recognizes the GSDMB pore-forming domain. We clarify that IpaH7.8 targets human (but not mouse) GSDMD through a similar mechanism. The structure of full-length GSDMB suggests stronger autoinhibition than in other gasdermins9,10. GSDMB has multiple splicing isoforms that are equally targeted by IpaH7.8 but exhibit contrasting pyroptotic activities. Presence of exon 6 in the isoforms dictates the pore-forming, pyroptotic activity in GSDMB. We determine the cryo-electron microscopy structure of the 27-fold-symmetric GSDMB pore and depict conformational changes that drive pore formation. The structure uncovers an essential role for exon-6-derived elements in pore assembly, explaining pyroptosis deficiency in the non-canonical splicing isoform used in recent studies6,8. Different cancer cell lines have markedly different isoform compositions, correlating with the onset and extent of pyroptosis following GZMA stimulation. Our study illustrates fine regulation of GSDMB pore-forming activity by pathogenic bacteria and mRNA splicing and defines the underlying structural mechanisms.

Date: 2023
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DOI: 10.1038/s41586-023-05872-5

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