ABCD of Thyroid Hormone Action: After and Before Cloning of Deiodinase Genes

The identification of a tri-iodinated form of thyroid hormone T3 almost 70 years ago in the laboratories of Rosalind Pitt-Rivers and Jean Roche triggered a debate that continues to the present day regarding how the physiological concentrations of T3 and its tetra-iodinated analogue, T4, are controlled. Although T4 is more abundant than T3 in the circulation, T3 has much higher affinity for the thyroid hormone receptor and by the 1970s, T3 was recognized as the primary active form of thyroid hormone. Over the succeeding decades, the pressing question of what controls levels of T3 prompted a search for enzymes that metabolize T4, T3, and other iodothyronine metabolites. Distinct deiodination activities were described that convert T4 into T3 (activation) and that convert T4 and T3 into largely inactive metabolites (inactivation). The clear implication was that in addition to the output of T4 and T3 by the thyroid gland, these deiodinase enzymes in peripheral tissues contribute to determining T3 levels in the circulation.

Another key concept was that deiodinases might modulate not only circulating levels of T3 but also local content of T3 within target tissues, thereby intrinsically modifying tissue responses. A crucial breakthrough in support of these ideas was the identification of the genes encoding the deiodinase enzymes. This was no trivial task and, even with the advent of gene cloning techniques, the deiodinase genes remained elusive until the 1990s. The difficulties arose in part because the enzymes are selenoproteins that incorporate the rare amino acid selenocysteine. This year, 2021, is the 30th anniversary of the landmark identification of the type 1 deiodinase gene (DIO1) (1), which was followed by identification of the genes encoding the type 3 (DIO3) (2) and type 2 (DIO2) (3) deiodinases. Endocrinology has published a collection of mini-reviews to mark this occasion and to highlight some of the many new directions that have opened up from the study of these genes.

The cloning of the 3 deiodinase genes offers 3 notable examples of independent thought and perseverance in scientific discovery, as recounted in the article by Galton, Larsen, and Berry (4). This article includes background on key advances in the decades that led up to the identification of the genes. The genes were identified by Marla Berry, L. Banu, and Reed Larsen (Brigham and Women’s Hospital, Harvard Medical School) and by the groups of Val Galton and Don St. Germain (Dartmouth Medical School) in collaboration with the group of Don Brown (Carnegie Institution for Science, Baltimore). It is noteworthy that 2 of the genes were first cloned from amphibian species, highlighting the indispensable place of basic research in model species in creating breakthroughs relevant to human physiology and disease. All 3 genes are conserved and the article by Darras (5) reviews the comparative biology and evolutionary context of deiodinases in non-mammalian species.

An observation made before the genes were cloned was that the type 2 (activating) and type 3 (inactivating) deiodinase activities are often expressed in dynamic, inverse patterns in development. The article by Hernandez et al (6) expands on this theme and reviews mammalian genetic studies that reveal major developmental functions for deiodinases in the hypothalamic-pituitary-thyroid axis, brain, and reproductive and sensory systems. The authors compare functions of the mouse and human genes, although so far, in humans, evidence is limited.

Deiodinases also play a role in the function of diverse mature tissues. The article by van der Spek et al (7) discusses the contribution of deiodinases to the function of innate immune cells, specifically neutrophil and macrophage lineages. The article by Russo et al (8) reviews the critical and complex roles of deiodinases in metabolic systems, including brown adipose tissue, liver, skeletal muscle, and pancreas. The article by Nappi et al (9) reviews deiodinases in cancer and a correlation between deiodinase expression and proliferative status during tumor progression. The authors discuss how further studies may suggest future diagnostic or therapeutic approaches. A companion article to this collection is the review by Köhrle (10) of the specialized selenoprotein family, to which all 3 deiodinases belong.

Collectively, these articles offer a glimpse into the remarkable insights made possible by the cloning of the deiodinase genes. The field continues to expand and, considering the pleiotropic actions of thyroid hormone, we may have only scratched the surface of understanding how deiodinases influence both normal tissue function and disease. The field has reached a stage that allows investigation not only of development and homeostasis but also of specific cellular responses to stress, injury, infection or other forms of disease, or physiological challenge. We may anticipate further advances relevant to human disorders and possible discoveries concerning human mutations. Future studies may delineate more precisely the extent to which deiodinases contribute to variations in circulating T4 and T3 levels, a critical clinical reference, that relates to optimal treatment of thyroid disorders.

Additional Information

Disclosure: The authors have nothing to disclose.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.