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PP2A regulates HDAC4 nuclear import

Gabriela Paroni1, Nadia Cernotta, Claudio Dello Russo

  • 1Dipartimento di Scienze e Tecnologie Biomediche, Sezione di Biologia and MATI Center of Excellence, Universita' di Udine, 33100 Udine, Italy.

Molecular Biology of the Cell
|November 30, 2007
PubMed

Insights

Protein phosphatase 2A (PP2A) dephosphorylates histone deacetylase 4 (HDAC4), promoting its nuclear entry. This dephosphorylation is crucial for regulating gene repression by class II HDACs.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cell Biology

Background:

  • Class II histone deacetylases (HDACs) regulate gene transcription through phosphorylation-dependent nuclear export.
  • Mechanisms controlling the nuclear import and gene repression activity of class II HDACs remain largely unknown.
  • Phosphatases are hypothesized to play a role in promoting nuclear entry of class II HDACs.

Purpose of the Study:

  • To investigate the role of phosphatases in the nuclear import of class II HDACs.
  • To identify the specific phosphatase involved in regulating HDAC4 nuclear localization.
  • To elucidate the molecular mechanisms by which PP2A controls HDAC4 nuclear entry.

Main Methods:

  • Co-immunoprecipitation assays to detect protein complex formation.
  • In vitro and in vivo binding studies to map interaction domains.
  • Treatment with okadaic acid (a PP2A inhibitor) and RNA interference to assess PP2A's role.
  • Site-directed mutagenesis to investigate the function of serine 298.

Main Results:

  • HDAC4 forms a stable complex with the PP2A holoenzyme.
  • The N-terminus of HDAC4 interacts with the catalytic subunit of PP2A.
  • PP2A dephosphorylates HDAC4, promoting its nuclear import.
  • Serine 298 is identified as a critical site for HDAC4 nuclear import; mimicking its phosphorylation impairs import.
  • Mutation of serine 298 partially restores nuclear import in PP2A-depleted cells.

Conclusions:

  • Protein phosphatase 2A (PP2A) directly interacts with and dephosphorylates HDAC4.
  • PP2A-mediated dephosphorylation of HDAC4, including at serine 298, is essential for its nuclear import.
  • This mechanism links PP2A activity to the regulation of gene repression by class II HDACs.

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