Fast skeletal muscle troponin I is a co-activator of estrogen receptor-related receptor α

Abstract ERRα (estrogen receptor-related receptor α) is a member of the nuclear receptor superfamily. To further our understanding of the detailed molecular mechanism of transcriptional regulation by ERRα, we searched for ERRα-interacting proteins using a yeast two-hybrid system by screening a human mammary gland cDNA expression library with the ligand-binding domain (LBD) of ERRα as the “bait”. Fast skeletal muscle troponin I (TNNI2), along with several known nuclear receptor co-activators, were isolated. We demonstrated that TNNI2 localizes to the cell nucleus and interacts with ERRα in co-immunoprecipitation experiments. GST pull-down assays also revealed that TNNI2 interacts directly with ERRα. Through luciferase reporter gene assays, TNNI2 was found to enhance the transactivity of ERRα. Combining mutagenesis and yeast two-hybrid assays, we mapped the ERRα-interacting domain on TNNI2 to a region encompassing amino acids 1–128. These findings reveal a new function for TNNI2 as a co-activator of ERRα.