PBF is a novel regulator of the thyroid hormone transporter MCT8

Within the basolateral membrane of thyroid follicular epithelial cells, two transporter proteins are important for thyroid hormone (TH) biosynthesis. Initially, sodium iodide symporter (NIS) delivers iodide from the bloodstream into the thyroid and, following biosynthesis, monocarboxylate transporter 8 (MCT8) mediates secretion of TH from the thyroid gland. NIS-mediated radioiodine uptake is also critical in the treatment of thyroid tumours and metastases. We have previously demonstrated that PTTG-binding factor (PBF), a proto-oncogene upregulated in thyroid cancer, binds NIS and modulates its subcellular localisation, impacting on its ability to uptake iodide. We have now investigated a potential relationship between PBF and MCT8. A physical interaction between PBF and MCT8 was demonstrated in vitro using GST-pulldown and co-immunoprecipitation assays. Further, immunofluorescent studies demonstrated a shift in subcellular localisation, with increased staining of MCT8 within intracellular vesicles following PBF over-expression in vitro. Within these vesicles, colocalisation between PBF and MCT8 was observed. A significant reduction in the amount of MCT8 at the plasma membrane was determined by cell surface biotinylation assays. Colocalisation between PBF and MCT8 was also observed in vivo in a mouse model of thyroid-specific PBF over-expression (PBF-Tg). Thyroidal MCT8 mRNA and protein expression were comparable with wild type mice. PBF-Tg mice developed significantly enlarged thyroid glands with both increased follicular diameter and thyroidal TH levels. Interestingly MCT8-KO mice also share this phenotype. These data show that PBF can bind and alter the subcellular localisation of MCT8. In vivo evidence suggests this may result in reduced TH secretion via MCT8. Overall, these studies identify PBF as a novel interacting partner of MCT8 and, alongside NIS repression, indicate that PBF may regulate TH biosynthesis and secretion.