Getting There: Thyroid Hormone Receptor Intracellular Trafficking

Abstract

Trafficking of regulatory proteins into and out of the nucleus is fundamental to the function of all living cells. A long-standing interest in my lab is exploring the diversity of signals regulating traffic control of the thyroid hormone receptors, TRα1 and TRβ1, transcription factors that either activate or repress the expression of target genes in response to thyroid hormone. Although primarily residing in the nucleus, TRα1 and TRβ1 shuttle rapidly between the nucleus and cytoplasm. Set against a backdrop of my path as a woman in STEM, milestones in our understanding of TR's pathway to the nucleus will be reviewed, while at the same time the innovative contributions of the diverse community of talented scientists in my lab will be showcased. Along the way, we have identified multiple nuclear localization signals (NLSs) and nuclear export signals (NESs) within TRα1 and TRβ1 that interact with importins and exportins, respectively, to mediate translocation across the nuclear envelope. To begin to understand the molecular mechanisms underlying TR's journey, we have focused on the role of post-translational modifications and interactions with transcriptional coregulators in modulating intracellular localization. Using a combined approach in transfected human cells of fluorescence-based nucleocytoplasmic scoring, fluorescence recovery after photobleaching (FRAP), overexpression, and knockdown studies, we have revealed that acetylation promotes cytoplasmic localization of TR, while Mediator subunit MED1 and nuclear receptor corepressor 1 (NCoR1) are key regulators of its nuclear retention. Given the pivotal role of TRα1 in human health, development, and metabolism, we hypothesized that in some types of cancer and endocrine disorders, TRα1's highly regulated traffic control may be disrupted. To analyze key structural components of TRα1 and to further explore the correlation between TRα1 trafficking, misfolding, and disease, recently we have examined the impact of cancer-associated and Resistance to Thyroid Hormone (RTH) syndrome mutations on TRα1 localization patterns. Results show striking shifts towards a more cytoplasmic localization for many of the mutants and an increased tendency to form cytoplasmic and nuclear aggregates. Although the journey is far from over, what has emerged so far is that the fine balance between nuclear import, nuclear retention, and nuclear export of TR is a critical control point for modulating the cellular response to thyroid hormone.