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Structural basis for GSDMB pore formation and its targeting by IpaH7.8

Chengliang Wang, Sonia Shivcharan, Tian Tian, Skylar Wright, Danyang Ma, JengYih Chang, Kunpeng Li, Kangkang Song, Chen Xu, Vijay A. Rathinam and Jianbin Ruan ()
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Chengliang Wang: University of Connecticut Health Center
Sonia Shivcharan: University of Connecticut Health Center
Tian Tian: University of Connecticut Health Center
Skylar Wright: University of Connecticut Health Center
Danyang Ma: University of Connecticut Health Center
JengYih Chang: University of Massachusetts Chan Medical School
Kunpeng Li: Case Western Reserve University School of Medicine
Kangkang Song: University of Massachusetts Chan Medical School
Chen Xu: University of Massachusetts Chan Medical School
Vijay A. Rathinam: University of Connecticut Health Center
Jianbin Ruan: University of Connecticut Health Center

Nature, 2023, vol. 616, issue 7957, 590-597

Abstract: Abstract Gasdermins (GSDMs) are pore-forming proteins that play critical roles in host defence through pyroptosis1,2. Among GSDMs, GSDMB is unique owing to its distinct lipid-binding profile and a lack of consensus on its pyroptotic potential3–7. Recently, GSDMB was shown to exhibit direct bactericidal activity through its pore-forming activity4. Shigella, an intracellular, human-adapted enteropathogen, evades this GSDMB-mediated host defence by secreting IpaH7.8, a virulence effector that triggers ubiquitination-dependent proteasomal degradation of GSDMB4. Here, we report the cryogenic electron microscopy structures of human GSDMB in complex with Shigella IpaH7.8 and the GSDMB pore. The structure of the GSDMB–IpaH7.8 complex identifies a motif of three negatively charged residues in GSDMB as the structural determinant recognized by IpaH7.8. Human, but not mouse, GSDMD contains this conserved motif, explaining the species specificity of IpaH7.8. The GSDMB pore structure shows the alternative splicing-regulated interdomain linker in GSDMB as a regulator of GSDMB pore formation. GSDMB isoforms with a canonical interdomain linker exhibit normal pyroptotic activity whereas other isoforms exhibit attenuated or no pyroptotic activity. Overall, this work sheds light on the molecular mechanisms of Shigella IpaH7.8 recognition and targeting of GSDMs and shows a structural determinant in GSDMB critical for its pyroptotic activity.

Date: 2023
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DOI: 10.1038/s41586-023-05832-z

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