New insights into thyroid hormone action

Abstract

Thyroid hormones (TH) are endocrine messengers essential for normal development and function of virtually every vertebrate. The hypothalamic-pituitary-thyroid axis is exquisitely modulated to maintain nearly constant TH (T4 and T3) levels in circulation. However peripheral tissues and the CNS control the intracellular availability of TH, suggesting that circulating concentrations of TH are not fully representative of what each cell type sees. Indeed, recent work in the field has identified that TH transporters, deiodinases and thyroid hormone receptor coregulators can strongly control tissue-specific sensitivity to a set amount of TH. Furthermore, the mechanism by which the thyroid hormone receptors regulate target gene expression can vary by gene, tissue and cellular context. This review will highlight novel insights into the machinery that controls the cellular response to TH, which include unique signaling cascades. These findings shed new light into the pathophysiology of human diseases caused by abnormal TH signaling.

Figure 1

The hypothalamus-pituitary-thyroid (HPT) axis maintains thyroid hormone homeostasis. The PVN neurons secret TRH in response to low circulating T3/T4 ratio. In turn, TRH signaling in the pituitary stimulates the secretion of TSH, which triggers the release of T4 and T3 from the thyroid gland into the bloodstream. T3 negative feedback upon expression of TRH and TSH genes in the PVN and the pituitary respectively keeps the T3/T4 ratio virtually constant in circulation.

Figure 2. The thyroid gland secretes T3 and T4 into the circulation

The thyroid follicular cells concentrate iodine within the colloid by using NIS/Pendrin transporters, which captures circulating I⁻ into the cytoplasm, followed by secretion to the colloid respectively. In the colloid the I⁻ is organified and coupled to thyroglobulin-tyrosine residues by TPO catalyzed oxidation, which requires of H₂O₂ generated by DUOX as cofactor; thus generating DIT and MIT, which form T4 and T3. TSH stimulation promotes endocytosis of the T4/T3-containing thyroglobulin, which releases the hormones after proteolysis in the cytosol. TSH receptor is coupled to G-protein and increases cAMP, which in turn is hydrolyzed by PDE8B. The MCT8 appears necessary for the transport of T4 from the thyroid gland while it and other transporters may play a role in T3 transport form the gland.

Figure 3. T3 modulates gene expression in virtually every vertebrate

T4/T3 circulates attached to serum proteins including thyroxine binding globulin (TBG) transthyretin (TTR), and albumin. A small fraction of circulating T4 is free to be transported into the cytoplasm, where it is activated to T3 by outer-ring deiodination catalyzed by Dio1 or Dio2. The resulting T3 is thought to be diffused into the nucleus to bind the thyroid hormone receptors (TR). Upon binding to the thyroid hormone receptors, T3 modulates the rate of mRNA synthesis and ultimately the protein levels of thousands of genes in virtually every cell.

Figure 4. T3 binds to the thyroid hormone receptors to modulate gene expression

In the absence of ligand the TR recruits NCoR1, which forms a multiprotein corepressor complex including Tbl1 and HDAC3. Binding of T3 induces the dismissal of the corepressor complex and allows the recruitment of coactivators (SRC1/CBP, CARM1/PRMT1), which include histone acetyl and methyl transferase activity thus facilitating the activation of the general transcription machinery and mRNA synthesis.

Figure 5. Schematic representation of the thyroid hormone receptor isoforms

TRs are encoded by the THRA and THRB genes, which produce multiple isoforms, Depicted are the major isoforms that modulated the actions of T3, with exception of TRalpha2 which does not bind T3 but acts as negative dominant by competing for the TRE with other TRs. TR isoforms share high sequence homology within their functional domains.

Figure 6. Corepressors and coactivators harbor nuclear receptor interacting domains

NCoR1 and SMRT harbor three nuclear receptor interacting domains; N3 and N2 interact preferentially with unliganded TR, whereas SRC harbors an RID that interacts with the TR upon adoption of liganded conformation.