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.
Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
Kuzhuvelil B
KB
Harikumar
Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
Jessie W
JW
Yester
Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
Michael J
MJ
Surace
Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
Clement
C
Oyeniran
Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
Megan M
MM
Price
Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
Wei-Ching
WC
Huang
Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
Nitai C
NC
Hait
Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
Jeremy C
JC
Allegood
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.
Akimitsu
A
Yamada
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Xiangqian
X
Kong
Department of Medicine, Department of Molecular Microbiology and Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
Helen M
HM
Lazear
Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
Reetika
R
Bhardwaj
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.
Kazuaki
K
Takabe
Department of Medicine, Department of Molecular Microbiology and Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
Michael S
MS
Diamond
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Cheng
C
Luo
Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
Sheldon
S
Milstien
Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
Sarah
S
Spiegel
Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
Tomasz
T
Kordula
D000818:Animals; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000276:immunology; D054357:Chemokine CXCL10 / Q000096:biosynthesis* / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D050856:Interferon Regulatory Factor-1 / Q000276:immunology / Q000378:metabolism*; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008239:Lysine; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D054875:Ubiquitination
D018946:Chemokine CCL5; D054357:Chemokine CXCL10; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D007375:Interleukin-1; C494258:Irf1 protein, mouse; D008239:Lysine