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

Nat Commun. 2021 Feb 19;12(1):1194. doi: 10.1038/s41467-021-21456-1.

Peng Gao ^# ¹, Xianwei Ma ^# ², Ming Yuan ^# ³, Yulan Yi ^# ¹, Guoke Liu ¹, Mingyue Wen ³, Wei Jiang ¹, Ruihua Ji ⁴, Lingxi Zhu ¹, Zhen Tang ¹, Qingzhuo Yu ¹, Jing Xu ¹, Rui Yang ⁴, Sheng Xia ⁵, Mingjin Yang ³, Jianping Pan ⁶, Hongbin Yuan ⁷, Huazhang An ⁸

Affiliations

1 Clinical Cancer Institute, Center for Translational Medicine, Second Military Medical University, Shanghai, 200433, China.
2 Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China.
3 Immunology Department & National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, 200433, China.
4 Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China.
5 Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
6 Department of Clinical Medicine, Zhejiang University City College School of Medicine, Hangzhou, 310015, China.
7 Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China. jfjczyy@163.com.
8 Clinical Cancer Institute, Center for Translational Medicine, Second Military Medical University, Shanghai, 200433, China. anhz@immunol.org.
# Contributed equally.

PMID: 33608556 DOI: 10.1038/s41467-021-21456-1

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.

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