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PMID: 22783022 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The Sin3a repressor complex is a master regulator of STAT transcriptional activity.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 109 ·No. 30 ·2012-07-24 ·Pages 12058-63

Icardi L, Mori R, Gesellchen V, Eyckerman S, De Cauwer L, Verhelst J, Vercauteren K, Saelens X, Meuleman P, Leroux-Roels G, De Bosscher K, Boutros M, Tavernier J

Abstract

Tyrosine phosphorylation is a hallmark for activation of STAT proteins, but their transcriptional activity also depends on other secondary modifications. Type I IFNs can activate both the ISGF3 (STAT1:STAT2:IRF9) complex and STAT3, but with cell-specific, selective triggering of only the ISGF3 transcriptional program. Following a genome-wide RNAi screen, we identified the SIN3 transcription regulator homolog A (Sin3a) as an important mediator of this STAT3-targeted transcriptional repression. Sin3a directly interacts with STAT3 and promotes its deacetylation. SIN3A silencing results in a prolonged nuclear retention of activated STAT3 and enhances its recruitment to the SOCS3 promoter, concomitant with histone hyperacetylation and enhanced STAT3-dependent transcription. 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.

MeSH Terms
Acetylation Animals Blotting, Western Cell Line Chromatin Immunoprecipitation DNA Primers/genetics Dogs Flow Cytometry Gene Expression Regulation/genetics,physiology Hepacivirus/metabolism Humans Immunoprecipitation Influenza A virus/metabolism Interferon-Stimulated Gene Factor 3, gamma Subunit/metabolism Luciferases Microarray Analysis Microscopy, Confocal RNA Interference Real-Time Polymerase Chain Reaction Repressor Proteins/metabolism STAT3 Transcription Factor/metabolism Sin3 Histone Deacetylase and Corepressor Complex Virus Internalization
Chemicals
DNA Primers IRF9 protein, human Interferon-Stimulated Gene Factor 3, gamma Subunit Repressor Proteins SIN3A transcription factor STAT3 Transcription Factor STAT3 protein, human Luciferases Sin3 Histone Deacetylase and Corepressor Complex
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Icardi Laura
Department of Medical Protein Research, Vlaams Instituut voor Biotechnologie, 9000 Ghent, Belgium.
Mori Raffaele
Gesellchen Viola
Eyckerman Sven
De Cauwer Lode
Verhelst Judith
Vercauteren Koen
Saelens Xavier
Meuleman Philip
Leroux-Roels Geert
De Bosscher Karolien
Boutros Michael
Tavernier Jan
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1206458109
Published
2012-07-24
Epub
2012-00-10
Pages
12058-63
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC3409767
Subset
IM
Databases
GEO
GSE35696
External Links
PubMed source DOI: 10.1073/pnas.1206458109 PMC Full Text View journal details
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