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

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, Chemokine CXCL10, Chemotaxis, Leukocyte, Enzyme-Linked Immunosorbent Assay, Humans, Immunoblotting, Immunoprecipitation, Inflammation, Interferon Regulatory Factor-1, Interleukin-1, Leukocytes, Mononuclear, Lysine, Mice, Mice, Knockout, Real-Time Polymerase Chain Reaction, Signal Transduction, Ubiquitination
Nat. Immunol.
Date: Mar. 01, 2014
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