ACAA2 is a ligand-dependent coactivator for thyroid hormone receptor β1

Thyroid hormones (THs) play a critical role in the metabolic phenotype of the heart; and most of the effects involve transcriptional regulation via thyroid hormone receptors (TRs). TRs ability to form combinatorial complexes with an array of partners accounts for TRs physiological flexibility in modulating gene expression. To identify proteins that associate with TRβ1 in the heart we performed a pull-down assay on cardiac tissue using GST-TRβ1 as bait and identified the bound proteins by LC MS/MS. ACAA2, a mitochondrial thiolase enzyme, was identified as a novel interacting protein. We confirmed ACAA2 localized to the nucleus and using a luciferase reporter assay showed ACAA2 acted as a TH-dependent coactivator for TRβ1. ACAA2 showed an ability to bind to TR recognition sequences but did not alter TRβ1 DNA binding ability. Thus, ACAA2 as a novel TRβ1 associating protein opens a new paradigm to understanding how TH/TRs may be manipulated by energetic pathway molecules.