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

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.
Mesh Terms:
Animals, Antiviral Agents, Baculoviral IAP Repeat-Containing 3 Protein, Catalysis, Cysteine, Female, HEK293 Cells, Humans, Immunity, Innate, Inhibitor of Apoptosis Proteins, Interferon Regulatory Factor-3, Interferon Type I, Mice, Mice, Inbred C57BL, Mice, Knockout, Nedd4 Ubiquitin Protein Ligases, Protein Processing, Post-Translational, Protein-Serine-Threonine Kinases, TNF Receptor-Associated Factor 3, Ubiquitin-Protein Ligases, Ubiquitination
Nat Commun
Date: Dec. 19, 2020
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