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.
Highlights
The innate immune system is the first line of host defense against pathogens [1]
We further found that dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 2 (DYRK2) phosphorylated Ser527 of TANK-binding kinase 1 (TBK1), which is essential for the recruitment of NLRP4 and for the E3 ubiquitin ligase DTX4 to degrade 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
Summary
A limited number of germline-encoded pattern-recognition receptors (PRRs), including the Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), NOD-like receptors (NLRs) and DNA receptors [1,2], recognize microbial components known as pathogen-associated molecular patterns (PAMPs) and trigger a series of signaling events that leads to the induction of type I interferons (IFNs) and proinflammatory cytokines [1,3]. Several DNA receptors have been identified, including RNA polymerase III, DAI, IFI16, DDX41, LSm14A and cGAS. Each of these DNA receptors requires a different adaptor to activate TBK1/IKKε to induce type I interferon expression in response to DNA [19,20,21,22,23,24]. PRR-induced expression of type I IFNs requires the key molecule TBK1 to activate the transcription factor IRF3
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