Proinflammatory stimuli induce IKKalpha-mediated phosphorylation of PIAS1 to restrict inflammation and immunity.
How inflammatory stimuli signal to the nucleus to restrict inflammation is poorly understood. Protein inhibitor of activated STAT1 (PIAS1), a transcriptional regulator that possesses small ubiquitin-related modifier (SUMO) E3 ligase activity, inhibits immune responses by selectively blocking the binding of NF-kappaB and STAT1 to gene promoters. We report here that PIAS1 becomes rapidly phosphorylated on Ser90 residue in response to various inflammatory stimuli. Mutational studies indicate that Ser90 phosphorylation is required for PIAS1 to repress transcription. Upon TNF treatment, wild-type PIAS1, but not the Ser90A mutant, becomes rapidly associated with the promoters of NF-kappaB target genes. Furthermore, IKKalpha, but not IKKbeta, interacts with PIAS1 in vivo and mediates PIAS1 Ser90 phosphorylation, a process that requires the SUMO ligase activity of PIAS1. Our results identify a signaling pathway in which proinflammatory stimuli activate the IKKalpha-mediated sumoylation-dependent phosphorylation of PIAS1 for the immediate repression of inflammatory gene activation.
Liu
Bin
B
Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Yang
Yonghui
Y
Chernishof
Vasili
V
Loo
Rachel R Ogorzalek
RR
Jang
Hyunduk
H
Tahk
Samuel
S
Yang
Randy
R
Mink
Sheldon
S
Shultz
David
D
Bellone
Clifford J
CJ
Loo
Joseph A
JA
Shuai
Ke
K
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology*; D008024:Ligands; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic
D008024:Ligands; C494211:Pias1 protein, mouse; D050828:Protein Inhibitors of Activated STAT; D034741:RNA, Small Interfering; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase