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Thyroid hormones, or THs, are well-known regulators of a wide range of biological processes that occur throughout the lifespan of all vertebrates. THs act through genomic mechanisms mediated by thyroid hormone receptors (TRs). The main product of the thyroid gland is thyroxine or T4, which can be further transformed by different biochemical pathways to produce at least 15 active or inactive molecules. T3, a product of T4 outer-ring deiodination, has been recognized as the main bioactive TH. However, growing evidence has shown that other TH derivatives are able to bind to, and/or activate TRs, to induce thyromimetic effects. The compiled data in this review points to at least two of these TR alternative ligands: TRIAC and T2. Taking this into account, non-mammalian models have proven to be advantageous to explore new TH derivatives with potential novel actions, prompting a re-evaluation of the role and mechanism of action of TR alternative ligands that were previously believed to be inactive. The functional implications of these ligands across different vertebrates may require us to reconsider current established notions of thyroid physiology.

T3 and cortisol activate or repress gene expression in virtually every vertebrate cell mainly by interacting with their nuclear hormone receptors. In contrast to the mechanisms for hormone gene activation, the mechanisms involved in gene repression remain elusive. In teleosts, the thyroid hormone receptor beta gene or thrb produces two isoforms of TRβ1 that differ by nine amino acids in the ligand-binding domain of the long-TRβ1, whereas the short-TRβ1 lacks the insert. Previous reports have shown that the genomic effects exerted by 3,5-T2, a product of T3 outer-ring deiodination, are mediated by the long-TRβ1. Furthermore, 3,5-T2 and T3 down-regulate the expression of long-TRβ1 and short-TRβ1, respectively. In contrast, cortisol has been shown to up-regulate the expression of thrb. To understand the molecular mechanisms for thrb modulation by thyroid hormones and cortisol, we used an in silico approach to identify thyroid- and cortisol-response elements within the proximal promoter of thrb from tilapia. We then characterized the identified response elements by EMSA and correlated our observations with the effects of THs and cortisol upon expression of thrb in tilapia. Our data show that 3,5-T2 represses thrb expression and impairs its up-regulation by cortisol possibly through a transrepression mechanism. We propose that for thrb down-regulation, ligands other than T3 are required to orchestrate the pleiotropic effects of thyroid hormones in vertebrates.

Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that activate or repress gene transcription, resulting in the regulation of numerous physiological programs. While 3,3',5-L-triiodothyronine is the TR cognate ligand, these receptors can also be activated by various alternative ligands, including endogenous and synthetic molecules capable of inducing diverse active receptor conformations that influence thyroid hormone-dependent signaling pathways. This review mainly discusses current knowledge on 3,5-diiodo-L-thyronine and 3,5,3'-triiodothyroacetic acid, two endogenous molecules that bind to TRs and regulate gene expression; and the molecular interactions between TRs and ligands, like synthetic thyromimetics developed to target specific TR isoforms for tissue-specific regulation of thyroid-related disorders, or endocrine disruptors that have allowed the design of new analogues and revealed essential amino acids for thyroid hormone binding.

The stereospecific removal of iodine from thyroid hormones is an essential first step for T3 action and is catalyzed by three different deiodinases: D2 and D3 remove iodine only from the outer or inner ring, respectively, whereas D1 catalyzes both pathways. We used in silico predictions from vertebrate deiodinase sequences to identify two domains: the N-terminal variable region (VR) containing the transmembrane, hinge and linker domains, and the conserved or globular region (CR). Given the high sequence and structural identity of the CR among paralogs as well as of the VR among orthologs but not paralogs, we hypothesized that both the catalytic properties and the subcellular localization rely on the VR. We used shark D2 and D3 as templates to build the chimeric enzymes D2VR/D3CR and D3VR/D2CR. Biochemical characterization revealed that D3VR/D2CR has inner-ring deiodination activity and T3 as preferred substrate, whereas D2VR/D3CR showed no deiodinating activity. Also, D2VR/D3CR and D3VR/D2CR reside in the endoplasmic reticulum and plasmatic membrane, respectively, as do their D2 and D3 wild-type counterparts. We conclude that the VR determines the subcellular localization and is critical in defining the catalytic properties and activity of thyroid hormone deiodinases.