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PKA phosphorylates histone deacetylase 5 and prevents its nuclear export, leading to the inhibition of gene transcription and cardiomyocyte hypertrophy
- Source :
- Proceedings of the National Academy of Sciences of the United States of America. 107(35)
- Publication Year :
- 2010
-
Abstract
- Dynamic nucleocytoplasmic shuttling of class IIa histone deacetylases (HDACs) is a fundamental mechanism regulating gene transcription. Recent studies have identified several protein kinases that phosphorylate HDAC5, leading to its exportation from the nucleus. However, the negative regulatory mechanisms for HDAC5 nuclear exclusion remain largely unknown. Here we show that cAMP-activated protein kinase A (PKA) specifically phosphorylates HDAC5 and prevents its export from the nucleus, leading to suppression of gene transcription. PKA interacts directly with HDAC5 and phosphorylates HDAC5 at serine 280, an evolutionarily conserved site. Phosphorylation of HDAC5 by PKA interrupts the association of HDAC5 with protein chaperone 14-3-3 and hence inhibits stress signal-induced nuclear export of HDAC5. An HDAC5 mutant that mimics PKA-dependent phosphorylation localizes in the nucleus and acts as a dominant inhibitor for myocyte enhancer factor 2 transcriptional activity. Molecular manipulations of HDAC5 show that PKA-phosphorylated HDAC5 inhibits cardiac fetal gene expression and cardiomyocyte hypertrophy. Our findings identify HDAC5 as a substrate of PKA and reveal a cAMP/PKA-dependent pathway that controls HDAC5 nucleocytoplasmic shuttling and represses gene transcription. This pathway may represent a mechanism by which cAMP/PKA signaling modulates a wide range of biological functions and human diseases such as cardiomyopathy.
- Subjects :
- Transcription, Genetic
Green Fluorescent Proteins
Immunoblotting
Molecular Sequence Data
Active Transport, Cell Nucleus
Histone Deacetylases
Substrate Specificity
Gene expression
Chlorocebus aethiops
medicine
Cyclic AMP
Animals
Humans
Myocytes, Cardiac
Amino Acid Sequence
Phosphorylation
Protein kinase A
Nuclear export signal
Cell Shape
Cells, Cultured
Cell Nucleus
Histone deacetylase 5
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
Multidisciplinary
biology
Sequence Homology, Amino Acid
Kinase
Colforsin
Biological Sciences
Rats
Cell nucleus
Histone
medicine.anatomical_structure
Biochemistry
Animals, Newborn
Microscopy, Fluorescence
COS Cells
biology.protein
Subjects
Details
- ISSN :
- 10916490
- Volume :
- 107
- Issue :
- 35
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....f53d51b46d105cee8dc0de847a3294b4