DYRK2 Negatively Regulates Type I Interferon Induction by Promoting TBK1 Degradation via Ser527 Phosphorylation

• Published in: PLoS pathogens Vol. 11; no. 9; p. e1005179
• Main Authors: An, Tai, Li, Shu, Pan, Wei, Tien, Po, Zhong, Bo, Shu, Hong-Bing, Wu, Shuwen
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.09.2015; Public Library of Science (PLoS)
• Subjects: Animals; Cytokines; Deoxyribonucleic acid; DNA; Dyrk Kinases; Enzyme-Linked Immunosorbent Assay; Health aspects; HEK293 Cells; HeLa Cells; Host-virus relationships; Humans; Immunoblotting; Immunoprecipitation; Infections; Interferon; Interferon Type I - biosynthesis; Interferon Type I - immunology; Kinases; Molecular Sequence Data; Observations; Phosphorylation; Plasmids; Polymerase Chain Reaction; Protein kinases; Protein Serine-Threonine Kinases - immunology; Protein Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - immunology; Protein-Tyrosine Kinases - metabolism; Regulation; RNA polymerase; RNA, Small Interfering; Serine - immunology; Serine - metabolism; Signal Transduction - immunology; Transcription factors; Transduction, Genetic; Viral infections; Virus Diseases - immunology; Virus Diseases - metabolism
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1005179

Viral infection activates the transcription factors NF-κB and IRF3, which contribute to the induction of type I interferons (IFNs) and cellular antiviral responses. Protein kinases play a critical role in various signaling pathways by phosphorylating their substrates. Here, we identified dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 2 (DYRK2) as a negative regulator of virus-triggered type I IFN induction. DYRK2 inhibited the virus-triggered induction of type I IFNs and promoted the K48-linked ubiquitination and degradation of TANK-binding kinase 1 (TBK1) in a kinase-activity-dependent manner. We further found that DYRK2 phosphorylated Ser527 of TBK1, which is essential for the recruitment of NLRP4 and for the E3 ubiquitin ligase DTX4 to degrade TBK1. These findings suggest that DYRK2 negatively regulates virus-triggered signaling by targeting TBK1 for phosphorylation and priming it for degradation, and these data provide new insights into the molecular mechanisms that dictate the cellular antiviral response.