E3 ligase Nedd4l promotes antiviral innate immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3

Peng Gao, Xianwei Ma, Ming Yuan, Yulan Yi, Guoke Liu, Mingyue Wen, Wei Jiang, Ruihua Ji, Lingxi Zhu, Zhen Tang, Qingzhuo Yu, Jing Xu, Rui Yang, Sheng Xia, Mingjin Yang, Jianping Pan, Hongbin Yuan () and Huazhang An ()
Additional contact information
Peng Gao: Second Military Medical University
Xianwei Ma: Shanghai Public Health Clinical Center, Fudan University
Ming Yuan: Second Military Medical University
Yulan Yi: Second Military Medical University
Guoke Liu: Second Military Medical University
Mingyue Wen: Second Military Medical University
Wei Jiang: Second Military Medical University
Ruihua Ji: Changzheng Hospital, Second Military Medical University
Lingxi Zhu: Second Military Medical University
Zhen Tang: Second Military Medical University
Qingzhuo Yu: Second Military Medical University
Jing Xu: Second Military Medical University
Rui Yang: Changzheng Hospital, Second Military Medical University
Sheng Xia: Jiangsu University
Mingjin Yang: Second Military Medical University
Jianping Pan: Zhejiang University City College School of Medicine
Hongbin Yuan: Changzheng Hospital, Second Military Medical University
Huazhang An: Second Military Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Ubiquitination is one of the most prevalent protein posttranslational modifications. Here, we show that E3 ligase Nedd4l positively regulates antiviral immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3. Deficiency of Nedd4l significantly impairs type I interferon and proinflammatory cytokine production induced by virus infection both in vitro and in vivo. Nedd4l deficiency inhibits virus-induced ubiquitination of TRAF3, the binding between TRAF3 and TBK1, and subsequent phosphorylation of TBK1 and IRF3. Nedd4l directly interacts with TRAF3 and catalyzes K29-linked ubiquitination of Cys56 and Cys124, two cysteines that constitute zinc fingers, resulting in enhanced association between TRAF3 and E3 ligases, cIAP1/2 and HECTD3, and also increased K48/K63-linked ubiquitination of TRAF3. Mutation of Cys56 and Cys124 diminishes Nedd4l-catalyzed K29-linked ubiquitination, but enhances association between TRAF3 and the E3 ligases, supporting Nedd4l promotes type I interferon production in response to virus by catalyzing ubiquitination of the cysteines in TRAF3.

Date: 2021
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DOI: 10.1038/s41467-021-21456-1

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