小柯机器人

中科院生物物理研究所丁璟珒等研究人员合作揭示调节GSDMB成孔活性的结构机制。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，细胞毒性淋巴细胞衍生的颗粒酶A（GZMA）切割GSDMB，一种gasdermin家族的成孔蛋白，从而触发靶细胞的焦亡。GSDMB和gasdermin家族成员GSDMD已被不一致地报道：被屈氏志贺菌泛素连接酶毒力因子IpaH7.8降解。IpaH7.8是否以及如何针对这两种gasdermin尚不明确，而GSDMB的焦亡功能最近甚至受到质疑。

研究人员报告了IpaH7.8-GSDMB复合物的晶体结构，它显示了IpaH7.8如何识别GSDMB的成孔结构域。研究人员澄清了IpaH7.8通过类似的机制靶向人类（而不是小鼠）GSDMD。全长的GSDMB结构表明比其他gasdermin有更强的自我抑制作用。GSDMB有多个拼接的异构体，它们同样是IpaH7.8的靶标，但表现出截然不同的焦亡活性。异构体中第6外显子的存在决定了GSDMB的成孔、焦亡活性。研究人员确定了27倍对称的GSDMB孔的冷冻电镜结构，并描述了驱动孔形成的构象变化。

该结构揭示了外显子6衍生的元件在孔组装中的重要作用，并解释了最近研究中使用的非经典剪接异构体的焦亡缺失。不同的癌细胞系有明显不同的异构体组成，与GZMA刺激后焦亡的发生和程度相关。这项研究说明了病原菌和mRNA剪接对GSDMB成孔活性的精细调节，并确定了基本的结构机制。

附：英文原文

Title: Structural mechanisms for regulation of GSDMB pore-forming activity

Author: Zhong, Xiu, Zeng, Huan, Zhou, Zhiwei, Su, Ya, Cheng, Hang, Hou, Yanjie, She, Yang, Feng, Na, Wang, Jia, Shao, Feng, Ding, Jingjin

Issue&Volume: 2023-03-29

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.

DOI: 10.1038/s41586-023-05872-5

Source: https://www.nature.com/articles/s41586-023-05872-5

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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