DYRK2 Negatively Regulates Type I Interferon Induction by Promoting TBK1 Degradation via Ser527 Phosphorylation
Open Access
- 25 September 2015
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Pathogens
- Vol. 11 (9), e1005179
- https://doi.org/10.1371/journal.ppat.1005179
Abstract
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. In recent years, the mechanisms of innate antiviral immune responses mediated by pattern recognition receptors (PRRs) have been heavily investigated. All PRRs require the key molecule TANK-binding kinase 1 (TBK1) to activate the transcription factor IRF3, which leads to type I interferon induction and the cellular antiviral response. Here, we identified the dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 2 (DYRK2) as a negative regulator of TBK1. DYRK2 inhibited the virus-triggered induction of type I interferon and promoted K48-linked ubiquitination and the degradation of TBK1 in a manner that depended on its kinase activity. 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. Our findings suggest that DYRK2 plays an important role in innate immune responses to viruses by modulating TBK1 activity and provide important insights into the intricate regulatory mechanisms of the innate immune response against viruses.Keywords
This publication has 67 references indexed in Scilit:
- Pathogen Recognition by the Innate Immune SystemInternational Reviews of Immunology, 2011
- Pattern Recognition Receptors and InflammationCell, 2010
- The interleukin‐1 receptor/Toll‐like receptor superfamily: 10 years of progressImmunological Reviews, 2008
- Pathogen Recognition and Innate ImmunityCell, 2006
- Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral responseNature, 2005
- Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6Nature, 2005
- Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling PathwayScience, 2003
- Identification of Lps2 as a key transducer of MyD88-independent TIR signallingNature, 2003
- Triggering the Interferon Antiviral Response Through an IKK-Related PathwayScience, 2003
- IKKε and TBK1 are essential components of the IRF3 signaling pathwayNature Immunology, 2003