Regulation of thyroid hormone receptor α2 RNA binding and subcellular localization by phosphorylation

Thyroid hormone receptor α2 (TRα2) is an alternative splice product of the TRα primary transcript whose unique carboxyl terminus does not bind T3 or activate transcription. The physiological function of TRα2 is unknown. We have found that TRα2 is a single stranded RNA binding protein and that the RNA binding domain localizes to a 41 amino acid region immediately distal to the second zinc finger. TRα2 contains a single protein kinase CK2 phosphorylation site in its amino terminus and potentially nine CK2 sites in its unique carboxyl terminus. In vitro CK2 treatment of TRα2 eliminated its RNA binding. Mutational analysis indicated that phosphorylations at the N- and C-terminal sites both contribute to this inhibitory effect. Cellular localization studies demonstrated that phosphorylated TRα2 is primarily cytoplasmic, whereas unphosphorylated TRα2 is primarily nuclear. Since RNA binding is a property of unphosphorylated TRα2, the TRα2-RNA interaction likely represents a nuclear function of TRα2.