Acetylation of Stat1 modulates NF-kappaB activity.
Acetylation of signaling molecules can lead to apoptosis or differentiation of carcinoma cells. The molecular mechanisms underlying these processes and the biological role of enzymes mediating the transfer or removal of an acetyl-group are currently under intense investigation. Our study shows that Stat1 is an acetylated protein. Stat1 acetylation depends on the balance between Stat1-associated histone deacetylases (HDACs) and histone acetyltransferases (HATs) such as CBP. Remarkably both inhibitors of HDACs and the cytokine interferon alpha alter this equilibrium and induce Stat1 acetylation. The analysis of Stat1 mutants reveals Lys 410 and Lys 413 as acetylation sites. Experiments with Stat1 mutants mimicking either constitutively acetylated or nonacetylated states show that only acetylated Stat1 is able to interact with NF-kappaB p65. As a consequence, p65 DNA binding, nuclear localization, and expression of anti-apoptotic NF-kappaB target genes decrease. These findings show how the acetylation of Stat1 regulates NF-kappaB activity and thus ultimately apoptosis.
Krämer
Oliver H
OH
Georg-Speyer-Haus, D-60596 Frankfurt, Germany.
Baus
Daniela
D
Knauer
Shirley K
SK
Stein
Stefan
S
Jäger
Elke
E
Stauber
Roland H
RH
Grez
Manuel
M
Pfitzner
Edith
E
Heinzel
Thorsten
T
D000107:Acetylation; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D051548:Histone Acetyltransferases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D046228:Microarray Analysis; D008856:Microscopy, Fluorescence; D009154:Mutation / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051996:Transcription Factor RelA / Q000378:metabolism*
D017931:DNA Primers; D056572:Histone Deacetylase Inhibitors; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D051996:Transcription Factor RelA; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases