Control of specificity and magnitude of NF-kappa B and STAT1-mediated gene activation through PIASy and PIAS1 cooperation.
NF-kappaB and STATs regulate multiple cellular processes through the transcriptional activation of genes with diversified functions. Although the molecular mechanisms that can turn on/off the overall NF-kappaB/STAT signaling have been extensively studied, how NF-kappaB/STAT-target genes can be differentially regulated is poorly understood. Here we report that PIASy, a member of the PIAS (for protein inhibitor of activated STAT) protein family, is a physiologically important transcriptional repressor of NF-kappaB and STAT1. Piasy deletion in dendritic cells resulted in enhanced expression of a subset of NF-kappaB and STAT1-dependent genes in response to LPS or IFN-gamma treatment, respectively. Consistently, Piasy null mice are hypersensitive to the LPS-induced endotoxic shock. Furthermore, PIASy and PIAS1 display specific as well as redundant effects on the regulation of NF-kappaB/STAT1 signaling. Pias1-/-Piasy-/- embryos died before day 11.5. The disruption of one allele of Pias1 in the Piasy-/- background significantly enhanced the effect of Piasy deletion on the transcriptional induction of NF-kappaB/STAT1-dependent genes, and vice versa. Our results demonstrate that PIASy cooperates with PIAS1 to regulate the specificity and magnitude of NF-kappaB/STAT1-mediated gene activation.
Tahk
Samuel
S
Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
Liu
Bin
B
Chernishof
Vasili
V
Wong
Kelly A
KA
Wu
Hong
H
Shuai
Ke
K
D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D050828:Protein Inhibitors of Activated STAT / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation
D016328:NF-kappa B; C494211:Pias1 protein, mouse; C414349:Piasy protein, mouse; D050828:Protein Inhibitors of Activated STAT; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse