Type 2 deiodinase at the crossroads of thyroid hormone action

Abstract

Thyroid hormone action can be customized on a cell-specific fashion through the controlled action of the deiodinase group of enzymes, which are homodimeric thioredoxin fold containing selenoproteins. Whereas the type II deiodinase (D2) initiates thyroid hormone signaling by activating the pro-hormone thyroxine (T4) to the biologically active T3 molecule, the type III deiodinase (D3) terminates thyroid hormone action by catalyzing the inactivation of both T4 and T3 molecules. Deiodinases play a role in thyroid hormone homeostasis, development, growth and metabolic control by affecting the intracellular levels of T3 and thus gene expression on a cell-specific basis. Whereas both Dio2 and Dio3 are transcriptionally regulated, ubiquitination of D2 is a switch mechanism that controls D2 activity and intracellular T3 production. The hedgehog-inducible WSB-1 and the yeast Doa10 mammalian ortholog TEB4 are two E3 ligases that inactivate D2 via ubiquitination. Inactivation involves disruption of the D2:D2 dimer and can be reversed via two ubiquitin-specific proteases, USP20 and USP33, rescuing catalytic activity and T3 production. The ubiquitin-based switch mechanism that controls D2 activity illustrates how different cell types fine-tune thyroid hormone signaling, making D2 a suitable target for pharmacological intervention. This article reviews the cellular and molecular aspects of D2 regulation and the current models of D2-mediated thyroid hormone signaling.

Figure 1

Thyroid hormone action is modulated by the deiodinases. T3 generated via D2-mediated deiodination acts via non-genomic mechanisms or the canonical nuclear thyroid hormone receptor pathway to regulate TSH and TRH secretion as well as cell development and metabolism. D3 terminates the thyroid hormone signaling pathway by inactivating T3 molecules into inactive substrates rT3 and/or T2.

Figure 2

D2 is a dimeric selenoenzyme ubiquitinated by WSB-1 and TEB4 complexes. (A) Ultra-structure of the D2:D2 dimer inserted into the ER membrane. Reproduced from (Sagar et al., 2007). (B) Detailed structure of the globular domain of D2. White asterisk marks the instability loop. Modified from (Dentice et al., 2005). In (C), newly synthesiZed D2 is targeted to the ER membrane, where D2 ubiquitination is triggered by T4-to-T3 catalysis. Ubiquitinated D2 (Ub-D2) is shuttled to the proteasomes. D2 can be rescued from terminal destruction via two DUBs: ubiquitin-specific proteases USP-20 and USP-33.