Extracellular fibrinogen-binding protein released by intracellular Staphylococcus aureus suppresses host immunity by targeting TRAF3

Xiaokai Zhang, Tingrong Xiong, Lin Gao, Yu Wang, Luxuan Liu, Tian Tian, Yun Shi, Jinyong Zhang, Zhuo Zhao, Dongshui Lu, Ping Luo, Weijun Zhang, Ping Cheng, Haiming Jing, Qiang Gou, Hao Zeng (), Dapeng Yan () and Quanming Zou ()
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Xiaokai Zhang: Third Military Medical University
Tingrong Xiong: Third Military Medical University
Lin Gao: Third Military Medical University
Yu Wang: Third Military Medical University
Luxuan Liu: Southwest Jiaotong University
Tian Tian: Third Military Medical University
Yun Shi: Sichuan University
Jinyong Zhang: Third Military Medical University
Zhuo Zhao: Third Military Medical University
Dongshui Lu: Third Military Medical University
Ping Luo: Third Military Medical University
Weijun Zhang: Third Military Medical University
Ping Cheng: Third Military Medical University
Haiming Jing: Third Military Medical University
Qiang Gou: Third Military Medical University
Hao Zeng: Third Military Medical University
Dapeng Yan: Fudan University
Quanming Zou: Third Military Medical University

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-33205-z

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