小柯机器人

美国康涅狄格大学Jianbin Ruan小组揭示GSDMB孔的形成及其被IpaH7.8靶向的结构基础。该项研究成果于2023年3月29日在线发表在《自然》杂志上。

研究人员表示，Gasdermin（GSDM）是一种成孔蛋白质，通过焦亡在宿主防御中发挥关键作用。在GSDM中，GSDMB是独特的，因为它具有独特的脂质结合特征，而且对其焦亡潜力缺乏共识。最近，GSDMB被证明可以通过其成孔的活性表现出直接的杀菌活性。志贺氏菌是一种细胞内的、适应人类的肠道病原体，它通过分泌IpaH7.8来逃避这种GSDMB介导的宿主防御，IpaH7.8是一种毒力效应物，会触发GSDMB的泛素化依赖性蛋白体降解。

研究人员报告了人GSDMB与志贺氏菌IpaH7.8和GSDMB孔复合的冷冻电镜结构。GSDMB-IpaH7.8复合物的结构确定了GSDMB中三个带负电荷的残基是IpaH7.8所识别的结构决定因素。人类而非小鼠的GSDMD含有这个保守的模体，解释了IpaH7.8的物种特异性。GSDMB孔结构显示，GSDMB中可变剪接调节的域间连接体是GSDMB孔形成的调节器。具有典型域间连接体的GSDMB异构体表现出正常的焦亡活性，而其他异构体则表现出减弱或没有焦亡活性。总的来说，这项工作揭示了志贺氏菌IpaH7.8识别和靶向GSDM的分子机制，并显示了GSDMB中对其焦亡活性至关重要的结构决定因素。

附：英文原文

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

Author: Wang, Chengliang, Shivcharan, Sonia, Tian, Tian, Wright, Skylar, Ma, Danyang, Chang, JengYih, Li, Kunpeng, Song, Kangkang, Xu, Chen, Rathinam, Vijay A., Ruan, Jianbin

Issue&Volume: 2023-03-29

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 potential3,4,5,6,7. 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.

DOI: 10.1038/s41586-023-05832-z

Source: https://www.nature.com/articles/s41586-023-05832-z

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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