Gβγ 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 Gβγ subunit of heterotrimeric G proteins, we found that Gβγ 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 Gβ1γ2-HDAC5 complex in mammalian cells can be blocked by overexpression of Gαo, and this inhibition is relieved by activation of α2A-adrenergic receptor, suggesting that the interaction occurs in a signal-dependent manner. The C-terminal domain of HDAC5 binds directly to Gβγ through multiple motifs, and overexpression of this domain mimics the C terminus of G protein-coupled receptor kinase 2, a known Gβγ scavenger, in its ability to inhibit the Gβγ/HDAC5 interaction. The C terminus of HDAC4 shares significant similarity with that of HDAC5, and accordingly, HDAC4 is also able to form complexes with Gβ1γ2 in cultured cells, suggesting that the C-terminal domain of class II HDACs is a general Gβγ binding motif. Activation of a Gi/o-coupled receptor results in a time-dependent activation of MEF2C, an HDAC5-regulated transcription factor, whereas inhibition of the interaction with a Gβγ 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 Gβγ effectors.