The Salmonella effector protein SopD targets Rab8 to positively and negatively modulate the inflammatory response

效应器 细胞生物学 分泌物 炎症 生物 促炎细胞因子 转运蛋白 GTP酶 小型GTPase 沙门氏菌 信号转导 免疫学 生物化学 遗传学 细菌
作者
Huan Lian,Kun Jiang,Ming Tong,Zhe Chen,Xiaoyu Liu,Jorge E. Galán,Xiang Gao
出处
期刊:Nature microbiology 卷期号:6 (5): 658-671 被引量:26
标识
DOI:10.1038/s41564-021-00866-3
摘要

The food-borne bacterial pathogen Salmonella Typhimurium uses a type III protein secretion system to deliver multiple proteins into host cells. These secreted effectors modulate the functions of host cells and activate specific signalling cascades that result in the production of pro-inflammatory cytokines and intestinal inflammation. Some of the Salmonella-encoded effectors counteract this inflammatory response and help to preserve host homeostasis. Here, we demonstrate that the Salmonella effector protein SopD, which is required for pathogenesis, functions to both activate and inhibit the inflammatory response by targeting the Rab8 GTPase, which is a negative regulator of inflammation. We show that SopD has GTPase-activating protein activity for Rab8 and, therefore, inhibits this GTPase and stimulates inflammation. We also show that SopD activates Rab8 by displacing it from its cognate guanosine dissociation inhibitor, resulting in the stimulation of a signalling cascade that suppresses inflammation. We solved the crystal structure of SopD in association with Rab8 to a resolution of 2.3 Å, which reveals a unique contact interface that underlies these complex interactions. These findings show the remarkable evolution of a bacterial effector protein to exert both agonistic and antagonistic activities towards the same host cellular target to modulate the inflammatory response. The Salmonella Typhimurium effector protein SopD is capable of both activating and inhibiting the host inflammatory response by modulating Rab8 GTPase.
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