Cellular and Molecular Basis of Deiodinase-Regulated Thyroid Hormone Signaling1
The iodothyronine deiodinases initiate or terminate thyroid hormone action and therefore are critical for the biological effects mediated by thyroid hormone. Over the years, research has focused on their role in preserving serum levels of the biologically active molecule T 3 during iodine deficiency. More recently, a fascinating new role of these enzymes has been unveiled. The activating deiodinase (D2) and the inactivating deiodinase (D3) can locally increase or decrease thyroid hormone signaling in a tissue-and temporal-specific fashion, independent of changes in thyroid hormone serum concentrations. This mechanism is particularly relevant be-cause deiodinase expression can be modulated by a wide variety of endogenous signaling molecules such as sonic hedgehog, nuclear factor-B, growth factors, bile acids, hypoxiainducible factor-1, as well as a growing number of xenobiotic substances. In light of these findings, it seems clear that deiodinases play a much broader role than once thought, with great ramifications for the control of thyroid hormone signaling during vertebrate development and metamorphosis, as well as injury response, tissue repair, hypothalamic function, and energy homeostasis in adults. (Endocrine Reviews 29: 898 -938, 2008) I. Introduction II. Structure and Cell Biology of Deiodinases A. Subcellular localization and structure B. Selenoprotein synthesis C. Posttranslational regulation of deiodinases III. Cellular Control of Thyroid Hormone Signaling A. Transport across membranes B. Deiodinase-mediated mechanisms C. Deiodination in intact cells and cofactor availability D. Conjugation of iodothyronine and its effects on deiodination pathways E. Deiodinases and thyronamines IV. Deiodinase-Mediated Thyroid Hormone Signaling in Discrete Cell Systems A. Development and metamorphosis B. Energy homeostasis C. Deiodinases in the hypothalamus/pituitary systems D. Transgenic murine models of ectopic D2 expression in the heart V. Deiodination in Disease States A. Local impact of altered deiodinase activity on thyroid hormone signaling in disease states B. Systemic impact of abnormal deiodinase activity on thyroid hormone homeostasis C. Genetic basis of deiodinase-related diseases VI. Conclusions