Gbetagamma interacts with enzymes involved in reversible protein acetylation

The βγ subunit of heterotrimeric G proteins is integral to an increasingly apparent number of cellular processes. Through a yeast 2‐hybrid screen, we recently discovered that Gβγ binds directly to the C‐terminus of histone deacetylase 5 (HDAC5), an enzyme involved in a pathway not previously recognized to be directly impacted by G proteins. The complex forms in a signal‐responsive manner in vivo and is inhibited by commonly used Gβγ scavengers such as Gαt and the C‐terminus of GPCR kinase 2. The interaction correlates with the ability of Gβγ overexpression or Gi activation to inhibit the transcriptional co‐repression activity of HDAC5 in in vivo assays. Thus, we propose that HDAC5, and possibly other related class II HDACs, can be added to the growing list of Gβγ effectors. Moreover, in studying the biological consequences of this interaction, we disovered that Gβγ interacts with a protein that functionally opposes HDAC activity, the histone acetylase Tip60. The Gβγ binding site on Tip60 is a surface adjacent to the enzyme’s active site, suggesting that complex formation may influence protein acetylation through direct modulation of catalytic activity. Reversible protein acetylation plays a central role in diverse processes, including the progression of diseases such as cancer and cardiac hypertrophy as well as the interplay between long term depression and facilitation in learning and memory. Thus, we hope that a greater understanding of the regulation of these pathways will lead to important advances in a number of fields.