Role of the type 2 iodothyronine deiodinase (D2) in the control of thyroid hormone signaling

Abstract

Background: Thyroid hormone signaling is critical for development, growth and metabolic control in vertebrates. Although serum concentration of thyroid hormone is remarkable stable, deiodinases modulate thyroid hormone signaling on a time- and cell-specific fashion by controlling the activation and inactivation of thyroid hormone.

Scope of the review: This review covers the recent advances in D2 biology, a member of the iodothyronine deiodinase family, thioredoxin fold-containing selenoenzymes that modify thyroid hormone signaling in a time- and cell-specific manner.

Major conclusions: D2-catalyzed T3 production increases thyroid hormone signaling whereas blocking D2 activity or disruption of the Dio2 gene leads to a state of localized hypothyroidism. D2 expression is regulated by different developmental, metabolic or environmental cues such as the hedgehog pathway, the adrenergic- and the TGR5-activated cAMP pathway, by xenobiotic molecules such as flavonols and by stress in the endoplasmic reticulum, which specifically reduces de novo synthesis of D2 via an eIF2a-mediated mechanism. Thus, D2 plays a central role in important physiological processes such as determining T3 content in developing tissues and in the adult brain, and promoting adaptive thermogenesis in brown adipose tissue. Notably, D2 is critical in the T4-mediated negative feed-back at the pituitary and hypothalamic levels, whereby T4 inhibits TSH and TRH expression, respectively. Notably, ubiquitination is a major step in the control of D2 activity, whereby T4 binding to and/or T4 catalysis triggers D2 inactivation by ubiquitination that is mediated by the E3 ubiquitin ligases WSB-1 and/or TEB4. Ubiquitinated D2 can be either targeted to proteasomal degradation or reactivated by deubiquitination, a process that is mediated by the deubiquitinases USP20/33 and is important in adaptive thermogenesis.

General significance: Here we review the recent advances in the understanding of D2 biology focusing on the mechanisms that regulate its expression and their biological significance in metabolically relevant tissues. This article is part of a Special Issue entitled Thyroid hormone signalling.

Fig. 1

D2 is regulated at the post-transcriptional level. The short-lived dimeric enzyme type 2 iodothyronine deiodinase (D2) is an endoplasmic reticulum (ER) resident protein regulated by the ubiquitin–proteasome pathway. (A) D2 ubiquitination is triggered by substrate (T4 or rT3) binding to D2’s catalytic core, when two different E3 ubiquitin ligases, WSB-1 and TEB4, play key roles in regulating cellular D2 levels. Ubiquitinated D2 complexes (Ub-D2) are catalytically inactive and can either be de-ubiquitinated by the action of the deubiquitinates (DUBs) USP20 and USP30, rescuing D2 activity; or are directed to the 26S proteasomal complex for terminal degradation. Besides ubiquitination, cellular D2 levels are regulated at the translational level by the ER stress pathway, which blocks D2 protein synthesis upon disruption of ER homeostasis and activation of the PERK–eIF2a pathway. Conversely, ER stress can be attenuated or even reversed by treatment of cells with chemical chaperones, thus lifting the negative effect of ER stress on D2 synthesis and finally increasing D2 activity. In (B), immunocytochemistry staining and confocal imaging of HEK-293 cells stably expressing a YFP-D2 construct. From left to right: nuclei (DAPI, blue); ERp72, an ER marker (green); and D2 (red). The overlay of all signals (yellow) is shown on the last picture on the right.

Fig. 2

D2 is expressed in skeletal muscle and is involved in muscle differentiation and regeneration. T4 and T3 reach the myoplasm by MCT8/10-mediated transport [115]. T4-to-T3 activation is mediated by the type 2 deiodinase (D2), whereby T3 acts by binding to nuclear thyroid hormone receptors (TRs) and activates the expression of key muscle proteins, such as myosin heavy chain (MHC) and sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA). Muscle D2 is subject to regulation by (i) bile acids via the TGR5–cAMP pathway, and (ii) via adrenergic stimulation [109]. In addition, D2-generated T3 could reach the blood stream via the iodothyronine transporters and contribute to serum T3 supplies. After muscle injury, muscle precursor cells (here represented by satellite cells – SC) are activated and D2 expression and D2-dependent T3 production are upregulated locally, driving differentiation and complete skeletal muscle regeneration via T3-dependent expression of MyoD, a master myogenic regulatory factor. In the figure: SR, sarcoplasmic reticulum and TGR5, G protein-coupled bile acid receptor 1 (GPBAR1).

Fig. 3

Schematic illustration of the D2 participation on the feedback system regulation of hypothalamic–pituitary axis (HPT). In the hypothalamus, D2 is strategically located on the lining floor and infralateral wall of the third ventricle (III), near TRH-expressing hypophysiotropic neurons located in the paraventricular nucleus (PVN). In the anterior pituitary gland, D2 is co-expressed with TSH in pituitary thyrotrophs. The drop in serum T3 is sensed by TRH-expressing hypophysiotropic neurons in the PVN and the pituitary TSH-secreting thyrotrophs, de-repressing the expression of TRH and TSH-β genes, respectively. In contrast, the drop in serum T4 can only de-repress TRH and TSH thanks to D2, which translates the serum T4 signal by locally converting it to T3 in the PVN and in the pituitary thyrothrophs, therefore establishing an important signaling pathway that controls thyroid hormone economy.