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. [email protected].
  • 8. Clinical Cancer Institute, Center for Translational Medicine, Second Military Medical University, Shanghai, 200433, China. [email protected].
  • # 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.