G betagamma binds histone deacetylase 5 (HDAC5) and inhibits its transcriptional co-repression activity.
In a yeast two-hybrid screen designed to identify novel effectors of the G betagamma subunit of heterotrimeric G proteins, we found that G betagamma binds to histone deacetylase 5 (HDAC5), an enzyme involved in a pathway not previously recognized to be directly impacted by G proteins. Formation of the G ... beta1gamma2-HDAC5 complex in mammalian cells can be blocked by overexpression of G alpha(o), and this inhibition is relieved by activation of alpha2A-adrenergic receptor, suggesting that the interaction occurs in a signal-dependent manner. The C-terminal domain of HDAC5 binds directly to G betagamma through multiple motifs, and overexpression of this domain mimics the C terminus of G protein-coupled receptor kinase 2, a known G betagamma scavenger, in its ability to inhibit the G betagamma/HDAC5 interaction. The C terminus of HDAC4 shares significant similarity with that of HDAC5, and accordingly, HDAC4 is also able to form complexes with G beta1gamma2 in cultured cells, suggesting that the C-terminal domain of class II HDACs is a general G betagamma binding motif. Activation of a G(i/o)-coupled receptor results in a time-dependent activation of MEF2C, an HDAC5-regulated transcription factor, whereas inhibition of the interaction with a G betagamma scavenger inhibits MEF2C activity, suggesting a reduced potency of HDAC5-mediated inhibition. Taken together, these data imply that HDAC5 and possibly other class II HDACs can be added to the growing list of G betagamma effectors.
Mesh Terms:
Amino Acid Motifs, Animals, Blotting, Western, Cattle, Cell Line, GTP-Binding Protein beta Subunits, GTP-Binding Protein gamma Subunits, Genes, Reporter, Histone Deacetylases, Humans, Immunoprecipitation, Mice, Plasmids, Protein Binding, Protein Structure, Tertiary, Rats, Rats, Sprague-Dawley, Receptors, Adrenergic, alpha-2, Repressor Proteins, Signal Transduction, Time Factors, Transcription, Genetic, Transfection, Two-Hybrid System Techniques
Amino Acid Motifs, Animals, Blotting, Western, Cattle, Cell Line, GTP-Binding Protein beta Subunits, GTP-Binding Protein gamma Subunits, Genes, Reporter, Histone Deacetylases, Humans, Immunoprecipitation, Mice, Plasmids, Protein Binding, Protein Structure, Tertiary, Rats, Rats, Sprague-Dawley, Receptors, Adrenergic, alpha-2, Repressor Proteins, Signal Transduction, Time Factors, Transcription, Genetic, Transfection, Two-Hybrid System Techniques
J. Biol. Chem.
Date: Dec. 16, 2005
PubMed ID: 16221676
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