The TAK1-JNK cascade is required for IRF3 function in the innate immune response

Cell Res. 2009 Apr;19(4):412-28. doi: 10.1038/cr.2009.8.


Interferon regulatory factor (IRF)3 is critical for the transcriptional induction of chemokines and cytokines during viral or bacterial invasion. The kinases Tank binding kinase (TBK)1 and Ikappa B kinase (IKK)epsilon can phosphorylate the C-terminal part of IRF3 and play important roles in IRF3 activation. In this study, we show that another kinase, c-Jun-NH(2)-terminal kinase (JNK), phosphorylates IRF3 on its N-terminal serine 173 residue, and TAK1 can stimulate IRF3 phosphorylation via JNK. JNK specific inhibitor SP600125 inhibits the N-terminal phosphorylation without affecting the C-terminal phosphorylation. In addition, IRF3-mediated gene expressions on lipopolysaccharide (LPS) or polyinosinic-cytidylic acid (polyI:C) treatment are severely impaired by SP600125, as well as for reporter gene assay of IRF3 activation. Knockdown of TAK1 further confirmed these observations. Interestingly, constitutive active IRF3(5D) can be inhibited by SP600125; JNK1 can synergize the action of IRF3(5D), but not the S173A-IRF3(5D) mutant. More importantly, polyI:C failed to induce the phosphorylation of mutant S173A and SP600125 dramatically abrogated IRF3 phosphorylation and dimerization that was stimulated by polyI:C. Thus, this study demonstrates that the TAK1-JNK cascade is required for IRF3 function, in addition to TBK1/IKKvarepsilon, uncovering a new mechanism for mitogen-activated protein (MAP) kinase to regulate the innate immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Anthracenes / chemistry
  • Anthracenes / pharmacology
  • Cell Line
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Humans
  • Immunity, Innate*
  • Interferon Regulatory Factor-3 / metabolism*
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Lipopolysaccharides / pharmacology
  • MAP Kinase Signaling System
  • Mice
  • Mutant Proteins / metabolism
  • Poly I-C / pharmacology
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA, Small Interfering / metabolism


  • Anthracenes
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Lipopolysaccharides
  • Mutant Proteins
  • RNA, Small Interfering
  • pyrazolanthrone
  • Protein Serine-Threonine Kinases
  • TBK1 protein, human
  • JNK Mitogen-Activated Protein Kinases
  • Poly I-C