TRαΔ1 is not an inhibitor of nuclear TRα signaling

Introduction: The thyroid hormone receptor (TR) α is important for physiology and homeostasis, especially for heart rate, body temperature and development of intestinal mucosa. TRα canonically acts as a ligand-dependent transcription factor. Twentyfive years ago, a truncated transcription variant of TRα, TRαΔ1, was identified. This variant lacks the nuclear localization sequence (NLS) and the DNA-binding domain (DBD) and the ligand binding domain is incomplete. At that time, it was reported that TRαΔ1 is localized in the cytosol as well as in the nucleus and inhibits the effect of regular TRα on gene expression. Since TRαΔ1 lacks the NLS and the DBD we questioned the inhibitory role attributed to TRαΔ1.

Material and Methods: Transcriptional activity or TRα and TRαΔ1 was determined with luciferase reporter assays. A dominant negative mutant with impaired T3 binding was used as control (TRαG291R). FLAG-tagged TRα and TRαΔ1 were transfected into HeLa cells. Subcellular localization was studied with confocal microscopy.

Results: In HeLa cells, TRαΔ1 did not inhibit the transcriptional activity of TRα. This was confirmed in several other cell lines. Furthermore, confocal microscopy showed that TRαΔ1 is only located in the cytoplasm and not in the nucleus.

Conclusion: These results are discrepant from early reports on TRαΔ1 but in agreement with the absence of an NLS and DBS in TRαΔ1. Therefore, TRαΔ1 is not an inhibitor of canonical TRα signaling and its physiological role needs to be rethought.