Thyroid hormone modulates gene expression in virtually every vertebrate cell through ligand-dependent transcription factors, the T3 receptors. Thyroid hormone is secreted as a pro-hormone (T4) that can be activated to T3 in a stage- and tissue-specific manner by two iodothyronine deiodinases, D1 and D2, while a third deiodinase, D3, prevents T4 activation and terminates T3 action. These three deiodinases are dimeric integral membrane selenoproteins composed of a single N-terminal trans-membrane segment connected to a larger globular domain that contains the active center embedded in a thioredoxin fold. A striking feature of this pocket is the presence of the rare amino acid Selenocysteine (Sec) that is critical for catalysis.

D2 is the key thyroid hormone activating enzyme, located in the brain, pituitary gland, brown adipose tissue and other important sites. It is localized in the endoplasmic reticulum (ER) and thus has the potential to increase the supply of T3 to the cell nucleus, directly affecting the expression of T3-responsive genes. D2 regulation is achieved by transcriptional control and also by ubiquitination, i.e. the covalent attachment of mono- or polyubiquitin chains to proteins, a critical step by which the function and fate of proteins may be altered. Ubiquin conjugation to D2 (Ub-D2) is catalyzed by UBC6 or UBC7 in yeast and mammalian cells, a step that inactivates D2 and targets it for degradation in the proteasomes. However, inactive Ub-D2 can be reactivated by the USP33 and USP20 deubiquitinating enzymes and rescued from terminal proteasomal degradation.

D2 ubiquitination is mediated by WSB-1, a SOCS-box-containing WD-40 protein that is induced by hedgehog signaling in embryonic structures during development and in some adult cells. WSB-1 is the substrate recognition subunit of a much larger ubiquitinating catalytic core complex, modeled as Elongin BC-Cul5-Rbx1 (ECSWSB-1). D2 is also ubiquitinated via Doa10 in yeast and its mammalian counterpart TEB4, a large ER-resident ligase that is involved in unfolding protein response. Thus, in developmental settings and in the brain, hedgehog-stimulated D2 ubiquitination locally decreases thyroid hormone signaling and thus the expression of T3-responsive genes.

D3 inactivates thyroid hormone and is expressed predominantly during development. In adults, D3 is expressed predominantly in the brain, skin and placenta, although low D3 activity has been reported in a number of tissues. D3 is normally present in the plasma membrane where it undergoes internalization and recycling with early endosomes. However, under hypoxic and/or ischemic conditions, D3 is redirected to the nuclear envelope where it inactivates T3 and decreases the metabolic impact of thyroid hormone. D3 is mainly transcriptionally regulated by TGFb, the hedgehog signaling pathway and HIF1a.

Deiodinase-mediated thyroid hormone activation or inactivation take place in metabolically relevant tissues such as hypothalamus, brown adipose tissue, skeletal muscle, liver and pancreatic b-cells. Mammals can rapidly increase the utilization of energy substrates and metabolic rate in response to different signals, including thyroid hormone. At the same time, low levels of thyroid hormone can slow down the rate of energy utilization. However, serum T3 levels are relatively constant in healthy subjects, a finding that is not surprising considering that T3 is such a pleiotropic molecule. Thus, deiodinases allow for the regulation of nuclear T3 in these metabolic tissues independently of changes in serum T3 levels. Targeted disruption of the Dio2 gene in mice is associated with impaired adaptive thermogenesis, cold intolerance and susceptibility to diet-induced obesity. At the same time, hypoxic injury to the brain and myocardium leads to HIF1-induced D3 expression, reducing thyroid hormone signaling and energy expenditure.