Non-Canonical Role of IKKα in the Regulation of STAT1 Phosphorylation in Antiviral Signaling

PLoS One. 2016 Dec 19;11(12):e0168696. doi: 10.1371/journal.pone.0168696. eCollection 2016.

Abstract

Non-self RNA is recognized by retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), inducing type I interferons (IFNs). Type I IFN promotes the expression of IFN-stimulated genes (ISGs), which requires the activation of signal transducer and activator of transcription-1 (STAT1). We previously reported that dsRNA induced STAT1 phosphorylation via a type I IFN-independent pathway in addition to the well-known type I IFN-dependent pathway. IκB kinase α (IKKα) is involved in antiviral signaling induced by dsRNA; however, its role is incompletely understood. Here, we explored the function of IKKα in RLR-mediated STAT1 phosphorylation. Silencing of IKKα markedly decreased the level of IFN-β and STAT1 phosphorylation inHeH response to dsRNA. However, the inhibition of IKKα did not alter the RLR signaling-mediated dimerization of interferon responsive factor 3 (IRF3) or the nuclear translocation of nuclear factor-κB (NFκB). These results suggest a non-canonical role of IKKα in RLR signaling. Furthermore, phosphorylation of STAT1 was suppressed by IKKα knockdown in cells treated with a specific neutralizing antibody for the type I IFN receptor (IFNAR) and in IFNAR-deficient cells. Collectively, the dual regulation of STAT1 by IKKα in antiviral signaling suggests a role for IKKα in the fine-tuning of antiviral signaling in response to non-self RNA.

MeSH terms

  • DEAD Box Protein 58 / genetics
  • DEAD Box Protein 58 / metabolism
  • HeLa Cells
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism*
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Type I / genetics
  • Interferon Type I / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Phosphorylation
  • RNA, Double-Stranded / genetics
  • RNA, Double-Stranded / metabolism
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / metabolism
  • Receptors, Immunologic
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism*
  • Signal Transduction*
  • Virus Diseases / genetics
  • Virus Diseases / metabolism*

Substances

  • IFNAR1 protein, human
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Interferon Type I
  • NF-kappa B
  • RNA, Double-Stranded
  • Receptors, Immunologic
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Receptor, Interferon alpha-beta
  • I-kappa B Kinase
  • RIGI protein, human
  • DEAD Box Protein 58

Grants and funding

The authors received no specific funding for this work.