Degradation of Thyroid Hormone Receptor Beta 1: Existence of Stable and Unstable Forms

Background: The degradation of many nuclear receptors is controlled by ligand-binding and mediated by the ubiquitin-proteasome pathway. However, the mechanisms implicated in thyroid hormone receptor (TR) degradation remain unclear. Our objective was to define the kinetics, mechanisms, and sub-cellular fractions involved in TRs degradation. Methods: We used pulse-chase analyses, time-course experiments carried out in presence of cycloheximide (to inhibit new protein synthesis), and biochemical fractionation with Western blot analyses to determine the kinetics of the degradation of the TR beta isoform, TR beta 1, in transiently transfected QBI-HEK 293A cells. Results: We observed that TR beta 1 degradation is mediated by the proteasome pathway. Also, the kinetics of TR beta 1 degradation is atypical due to the co-existence of more than one TR beta 1 population, located in different cellular compartments and having different stability profiles. Moreover, TR beta 1 degradation was unaffected by a mutation in its putative PEST motif, which confers turnover of other proteins. Conclusion: Our findings introduce novel evidence suggesting that stable and unstable forms of TR beta 1, which might have distinct functions, co-exist in cells.