Extracellular fibrinogen-binding protein released by intracellular Staphylococcus aureus suppresses host immunity by targeting TRAF3.
Extracellular fibrinogen-binding protein released by intracellular Staphylococcus aureus suppresses host immunity by targeting TRAF3.
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胞内金黄色葡萄球菌释放的 Efb 通过靶向 TRAF3 抑制宿主免疫
DOI：
10.1038/s41467-022-33205-z
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发表时间：
2022-09-19
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
许多病原体分泌效应蛋白，劫持宿主免疫细胞内的信号调节因子，以促进发病机制。然而，金黄色葡萄球菌分泌的效应蛋白在宿主细胞内的发病机制尚不清楚。在此，我们报告称金黄色葡萄球菌将细胞外纤维蛋白原结合蛋白（Efb）分泌到巨噬细胞的细胞质中，以抑制宿主免疫。从机制上讲，宿主E3连接酶环指蛋白114介导Efb第71位赖氨酸发生K27连接的泛素化，这有助于招募肿瘤坏死因子受体相关因子（TRAF）3。Efb与TRAF3的结合破坏了TRAF3/TRAF2/cIAP1（细胞凋亡抑制蛋白1）复合物的形成，该复合物介导TRAF3发生K48连接的泛素化以促进其降解，从而抑制炎症信号级联反应。此外，Efb K71R突变体丧失了抑制炎症的能力，且致病性降低。因此，我们的研究结果揭示了金黄色葡萄球菌抑制宿主防御的一种未知机制，这可能是开发有效的抗金黄色葡萄球菌免疫调节剂的一个有前景的靶点。
金黄色葡萄球菌分泌大量效应蛋白以逃避或抑制宿主免疫反应，然而这些效应蛋白操控巨噬细胞信号通路的潜在机制仍不明确。作者利用体外和体内模型来探究细胞外纤维蛋白原结合蛋白（Efb）在免疫反应调节和致病性中的作用。
Many pathogens secrete effectors to hijack intracellular signaling regulators in host immune cells to promote pathogenesis. However, the pathogenesis of Staphylococcus aureus secretory effectors within host cells is unclear. Here, we report that Staphylococcus aureus secretes extracellular fibrinogen-binding protein (Efb) into the cytoplasm of macrophages to suppress host immunity. Mechanistically, RING finger protein 114, a host E3 ligase, mediates K27-linked ubiquitination of Efb at lysine 71, which facilitates the recruitment of tumor necrosis factor receptor associated factor (TRAF) 3. The binding of Efb to TRAF3 disrupts the formation of the TRAF3/TRAF2/cIAP1 (cellular-inhibitor-of-apoptosis-1) complex, which mediates K48-ubiquitination of TRAF3 to promote degradation, resulting in suppression of the inflammatory signaling cascade. Additionally, the Efb K71R mutant loses the ability to inhibit inflammation and exhibits decreased pathogenicity. Therefore, our findings identify an unrecognized mechanism of Staphylococcus aureus to suppress host defense, which may be a promising target for developing effective anti-Staphylococcus aureus immunomodulators. Staphylococcus aureus secrete numerous effectors to evade or inhibit the host immune response, yet the mechanism underlying the effectors ability to manipulate the signalling pathways of macrophages remain unclear. Authors utilise in vitro and in vivo models to explore the role of extracellular fibrinogen-binding protein (Efb) in immune response modulation and pathogenicity.
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DOI：
10.1126/science.1256478
发表时间：
2014-12-05
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Sreeramkumar V;Adrover JM;Ballesteros I;Cuartero MI;Rossaint J;Bilbao I;Nácher M;Pitaval C;Radovanovic I;Fukui Y;McEver RP;Filippi MD;Lizasoain I;Ruiz-Cabello J;Zarbock A;Moro MA;Hidalgo A
通讯作者：
Hidalgo A
影响因子：
4.3
作者：
Joshi, Nikita;Walter, James M.;Misharin, Alexander V.
通讯作者：
Misharin, Alexander V.
影响因子：
81.5
作者：
Lee, Andie S.;de Lencastre, Herminia;Harbarth, Stephan
通讯作者：
Harbarth, Stephan
影响因子：
4.8
作者：
Gupta, Purnima;Giri, Jayeeta;Ukil, Anindita
通讯作者：
Ukil, Anindita
影响因子：
30.3
作者：
Nakagawa S;Matsumoto M;Katayama Y;Oguma R;Wakabayashi S;Nygaard T;Saijo S;Inohara N;Otto M;Matsue H;Núñez G;Nakamura Y
通讯作者：
Nakamura Y