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

Area of Science:

• Biochemistry
• Molecular Biology
• Cardiology

Background:

• Thyroid hormones (THs) are crucial for cardiac metabolic regulation, primarily through transcriptional control mediated by thyroid hormone receptors (TRs).
• TRs exhibit functional flexibility by forming diverse complexes with various partners, enabling precise modulation of gene expression.

Purpose of the Study:

• To identify novel protein interactors of the TRβ1 isoform within cardiac tissue.
• To investigate the functional role of identified interactors in TH-mediated transcriptional regulation.

Main Methods:

• Proteomic analysis using pull-down assays with GST-TRβ1 on cardiac tissue, followed by LC-MS/MS identification of bound proteins.
• Confirmation of protein localization via cellular imaging.
• Functional assessment using luciferase reporter assays to evaluate coactivator activity and DNA-binding interactions.

Main Results:

• ACAA2, a mitochondrial thiolase enzyme, was identified as a novel protein interacting with TRβ1 in the heart.
• ACAA2 was confirmed to localize to the nucleus and function as a TH-dependent coactivator for TRβ1.
• ACAA2 binds to TR recognition sequences without affecting TRβ1's DNA-binding capacity.

Conclusions:

• ACAA2 represents a novel TRβ1-associating protein, expanding our understanding of TH/TR signaling in the heart.
• The discovery of ACAA2 provides a new perspective on how energetic pathway molecules can influence TH/TR activity and cardiac metabolism.