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

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

Author information

1
Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
2
1] Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA. [2] Department of Surgery and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
3
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
4
Department of Medicine, Department of Molecular Microbiology and Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

Abstract

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.

PMID:
24464131
PMCID:
PMC3976678
DOI:
10.1038/ni.2810
[Indexed for MEDLINE]
Free PMC Article

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