K63-linked polyubiquitination of transcription factor IRF1 is essential for IL-1-induced production of chemokines CXCL10 and CCL5

Nat Immunol. 2014 Mar;15(3):231-8. doi: 10.1038/ni.2810. Epub 2014 Jan 26.


Although interleukin 1 (IL-1) induces expression of the transcription factor IRF1 (interferon-regulatory factor 1), the roles of IRF1 in immune and inflammatory responses and mechanisms of its activation remain elusive. Here we found that IRF1 was essential for IL-1-induced expression of the chemokines CXCL10 and CCL5, which recruit mononuclear cells into sites of sterile inflammation. Newly synthesized IRF1 acquired Lys63 (K63)-linked polyubiquitination mediated by the apoptosis inhibitor cIAP2 that was enhanced by the bioactive lipid S1P. In response to IL-1, cIAP2 and the sphingosine kinase SphK1 (the enzyme that generates S1P) formed a complex with IRF1, which led to its activation. Thus, IL-1 triggered a hitherto unknown signaling cascade that controlled the induction of IRF1-dependent genes that encode molecules important for sterile inflammation.

MeSH terms

  • Animals
  • Chemokine CCL5 / biosynthesis*
  • Chemokine CCL5 / immunology
  • Chemokine CXCL10 / biosynthesis*
  • Chemokine CXCL10 / immunology
  • Chemotaxis, Leukocyte / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Inflammation / immunology
  • Inflammation / metabolism
  • Interferon Regulatory Factor-1 / immunology
  • Interferon Regulatory Factor-1 / metabolism*
  • Interleukin-1 / immunology
  • Interleukin-1 / metabolism*
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Lysine
  • Mice
  • Mice, Knockout
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction / immunology*
  • Ubiquitination


  • Chemokine CCL5
  • Chemokine CXCL10
  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • Interleukin-1
  • Irf1 protein, mouse
  • Lysine