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Acetylation of Stat1 modulates NF-kappaB activity

Oliver H Krämer1, Daniela Baus, Shirley K Knauer

  • 1Georg-Speyer-Haus, D-60596 Frankfurt, Germany.

Genes & Development
|February 17, 2006
PubMed

Insights

Stat1 protein acetylation, regulated by histone deacetylases (HDACs) and histone acetyltransferases (HATs), impacts carcinoma cell apoptosis. Acetylated Stat1 inhibits NF-kappaB p65 activity, decreasing anti-apoptotic gene expression.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Acetylation of signaling molecules influences carcinoma cell apoptosis and differentiation.
  • The roles of histone deacetylases (HDACs) and histone acetyltransferases (HATs) in these processes are under active investigation.

Purpose of the Study:

  • To investigate the acetylation status of Signal Transducer and Activator of Transcription 1 (Stat1).
  • To elucidate the role of Stat1 acetylation in regulating the activity of Nuclear Factor kappa B (NF-kappaB).

Main Methods:

  • Analysis of Stat1 acetylation using inhibitors of HDACs and HATs, and interferon alpha.
  • Site-directed mutagenesis to identify Stat1 acetylation sites (Lys 410 and Lys 413).
  • Co-immunoprecipitation assays to assess Stat1 interaction with NF-kappaB p65.

Main Results:

  • Stat1 is identified as an acetylated protein, with acetylation levels modulated by the balance of HDACs and HATs (e.g., CBP).
  • Inhibitors of HDACs and interferon alpha induce Stat1 acetylation.
  • Acetylated Stat1 fails to interact with NF-kappaB p65, leading to reduced p65 DNA binding, nuclear localization, and expression of anti-apoptotic target genes.

Conclusions:

  • Stat1 acetylation is a critical regulatory mechanism controlling NF-kappaB activity.
  • Modulation of Stat1 acetylation influences the expression of NF-kappaB target genes, thereby impacting apoptosis in carcinoma cells.

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