P131 STAT transcriptional activity is controlled by regulated deacetylation

Tyrosine phosphorylation is a hallmark for activation of Signal Transducer and Activator of Transcription (STAT) proteins, but their transcriptional activity also depends on other secondary modifications. Type I interferons (IFNs) can activate both the ISGF3 (STAT1:STAT2:IRF9) complex and STAT3, but...

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Bibliographic Details
Published in:Cytokine (Philadelphia, Pa.) Pa.), 2012-09, Vol.59 (3), p.561-561
Main Authors: Icardi, L., Mori, R., Gesellchen, V., Eyckerman, S., Verhelst, J., Vercauteren, K., Saelens, X., Meuleman, P., Bosscher, K. De, Boutros, M., Tavernier, J.
Format: Article
Language:English
Subjects:
Acetylation
Cytokines
Deacetylation
DNA
HDAC2 protein
Hepatitis C
Histone deacetylase
Influenza A
Interferon
Phosphorylation
Reporter gene
Repressors
RNA-mediated interference
Stat protein
Stat1 protein
Stat3 protein
Transcription
Trichostatin A
Tyrosine
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Summary:Tyrosine phosphorylation is a hallmark for activation of Signal Transducer and Activator of Transcription (STAT) proteins, but their transcriptional activity also depends on other secondary modifications. Type I interferons (IFNs) can activate both the ISGF3 (STAT1:STAT2:IRF9) complex and STAT3, but with cell-specific, selective triggering of only the ISGF3 transcriptional program. Simultaneous treatment with IFNa2 and Trichostatin A, as well as combined HDAC1/HDAC2 silencing, restores STAT3-dependent reporter gene and endogenous genes expression, strongly suggesting that HDAC1 and HDAC2 are directly involved in repressing IFNa-activated STAT3. We used the IFN-dependent STAT3 transcriptional blockade as read-out for a genome-wide RNAi repressor screen. Quite significantly, we identified multiple partners of the Sin3a/HDAC transcriptional repressor complex as negative regulators of STAT3 transcriptional activity, regardless to the STAT3 activating stimulus. Sin3a directly interacts with STAT3 and controls its acetylation status, its nuclear accumulation and DNA binding, strongly influencing the transcription of a subset of STAT3-responsive genes. Conversely, Sin3a is required for ISGF3-dependent gene transcription and for an efficient IFN-mediated antiviral protection against influenza A and hepatitis C viruses. The Sin3a complex therefore acts as a context-dependent ISGF3/STAT3 transcriptional switch.
ISSN:1043-4666
1096-0023
DOI:10.1016/j.cyto.2012.06.223