Evolution of ligands, receptors and metabolizing enzymes of thyroid signaling

Abstract

Thyroid hormones (THs) play important roles in vertebrates such as the control of the metabolism, development and seasonality. Given the pleiotropic effects of thyroid disorders (developmental delay, mood disorder, tachycardia, etc), THs signaling is highly investigated, specially using mammalian models. In addition, the critical role of TH in controlling frog metamorphosis has led to the use of Xenopus as another prominent model to study THs action. Nevertheless, animals regarded as non-model species can also improve our understanding of THs signaling. For instance, studies in amphioxus highlighted the role of Triac as a bona fide thyroid hormone receptor (TR) ligand. In this review, we discuss our current understanding of the THs signaling in the different taxa forming the metazoans (multicellular animals) group. We mainly focus on three actors of the THs signaling: the ligand, the receptor and the deiodinases, enzymes playing a critical role in THs metabolism. By doing so, we also pinpoint many key questions that remain unanswered. How can THs accelerate metamorphosis in tunicates and echinoderms while their TRs have not been yet demonstrated as functional THs receptors in these species? Do THs have a biological effect in insects and cnidarians even though they do not have any TR? What is the basic function of THs in invertebrate protostomia? These questions can appear disconnected from pharmacological issues and human applications, but the investigation of THs signaling at the metazoans scale can greatly improve our understanding of this major endocrinological pathway.

ECOdrug: a database connecting drugs and conservation of their targets across species

“…To illustrate this, the ECOdrug predictions suggest that orthologs of the thyroid hormone receptors (THRA/THRB) are not present in Daphnia pulex , but do occur in some invertebrate deuterostomes (such as the sea urchin) and molluscs. These results align with a recent review on thyroid signaling conservation describing the presence of thyroid hormone receptors in invertebrate deuterostomes and nematodes—though they are not always responsive to thyroid hormone ( 29 ). In humans, defects in thyroid hormone signaling can lead to severe pathological conditions ( 30 ).…”

3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action

“…The existence of 3,5-T2 in thyroglobulin has not been clearly demonstrated (49,50) and appears biochemically improbable considering that TPO catalyzes coupling of mono-and/or di-iodinated tyrosine residues to yield either T4 or T3, while no such coupling was observed between diiodotyrosine and iodine-free tyrosine in reports available. Formation of iodothyronines outside of the thyroid gland has not been reported in humans or mammalian organisms while various aquatic life forms synthesize T4 without presenting the highly evolved follicular structure of thyroid glands in vertebrates (51). Circumstantial evidence using the DIO1 inhibitor PTU in isolated rat mitochondria or perfused rat liver led to the assumption that 3,5-T2 is a logical deiodinase product of T3 (16,52), but various attempts to demonstrate such a reaction in vitro failed to support this hypothesis.…”

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

“…TRα is ubiquitously expressed, while TRβ is mainly expressed in liver, pituitary, inner ear and some brain areas (Chatonnet et al 2013), but in particular because they regulate different sets of genes. TRs respond to iodinated biomolecules known as thyroid hormones (THs), mostly to the active form 3,3′,5-triiodol-thyronine (T3), which is generated in turn from the prohormone, l-thyroxine (T4) (Holzer et al 2017).…”