The Salmonella effector protein SopD targets Rab8 to positively and negatively modulate the inflammatory response.
The Salmonella effector protein SopD targets Rab8 to positively and negatively modulate the inflammatory response.
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沙门氏菌效应蛋白 SopD 以 Rab8 为靶标，正向和负向调节炎症反应
DOI：
10.1038/s41564-021-00866-3
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发表时间：
2021-05
影响因子：
28.3
通讯作者：
Gao X
中科院分区：
文献类型：
--
作者：
Lian H;Jiang K;Tong M;Chen Z;Liu X;Galán JE;Gao X
食源性细菌病原体鼠伤寒沙门氏菌使用III型蛋白质分泌系统将多种蛋白质递送到宿主细胞中。这些分泌的效应物调节宿主细胞功能并激活导致促炎细胞因子和肠道炎症产生的特异性信号级联。一些沙门氏菌编码的效应物对抗这种炎症反应，并有助于保持宿主体内平衡。我们证明，沙门氏菌效应蛋白SopD，这是必要的发病机制，功能激活和抑制炎症反应，通过靶向Rab8 GTdR，炎症的负调节。我们表明，SopD具有Rab8的GT3激活蛋白活性，因此抑制了这种GT3并刺激炎症。我们还表明，SopD激活Rab8取代其同源鸟苷解离抑制剂，导致刺激的信号级联反应，抑制炎症。我们解决了与Rab8相关的SopD的晶体结构，分辨率为2.3 nm，这揭示了这些复杂相互作用背后的独特接触界面。这些发现显示了细菌效应蛋白的显著进化，其对相同的宿主细胞靶标发挥激动和拮抗活性以调节炎症反应。
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 host cell functions and activate specific signalling cascades that result in the production of pro-inflammatory cytokines and intestinal inflammation. Some of the Salmonella-encoded effectors counter this inflammatory response and help to preserve host homeostasis. 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, 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 signaling cascade that suppresses inflammation. We solved the crystal structure of SopD in association with Rab8 to 2.3 Å resolution, which reveals a unique contact interface underlying these complex interactions. These findings show the remarkable evolution of a bacterial effector protein to exert both agonistic and antagonistic activities toward the same host cellular target to modulate the inflammatory response.
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影响因子：
6.7
作者：
Bruno VM;Hannemann S;Lara-Tejero M;Flavell RA;Kleinstein SH;Galán JE
通讯作者：
Galán JE
影响因子：
8.8
作者：
D'Costa, Vanessa M.;Braun, Virginie;Brumell, John H.
通讯作者：
Brumell, John H.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
48
作者：
Gibson, Daniel G.;Young, Lei;Smith, Hamilton O.
通讯作者：
Smith, Hamilton O.
影响因子：
3.4
作者：
Haraga, A;Miller, SI
通讯作者：
Miller, SI