Scope and limitations of iodothyronine deiodinases in hypothyroidism

Abstract

The coordinated expression and activity of the iodothyronine deiodinases regulate thyroid hormone levels in hypothyroidism. Once heralded as the pathway underpinning adequate thyroid-hormone replacement therapy with levothyroxine, the role of these enzymes has come into question as they have been implicated in both an inability to normalize serum levels of tri-iodothyronine (T3) and the incomplete resolution of hypothyroid symptoms. These observations, some of which were validated in animal models of levothyroxine monotherapy, challenge the paradigm that tissue levels of T3 and thyroid-hormone signalling can be fully restored by administration of levothyroxine alone. The low serum levels of T3 observed among patients receiving levothyroxine monotherapy occur as a consequence of type 2 iodothyronine deiodinase (DIO2) in the hypothalamus being fairly insensitive to ubiquitination. In addition, residual symptoms of hypothyroidism have been linked to a prevalent polymorphism in the DIO2 gene that might be a risk factor for neurodegenerative disease. Here, we discuss how these novel findings underscore the clinical importance of iodothyronine deiodinases in hypothyroidism and how an improved understanding of these enzymes might translate to therapeutic advances in the care of millions of patients with this condition.

Figure 1

Iodothyronine deiodinases modulate thyroid-hormone signalling in T₃ target cells. T₄ and T₃ enter almost all cells via membrane transporters and are then modified in a cell-specific manner by DIOs to either enhance (DIO2) or diminish (DIO3) thyroid-hormone signalling. Consequently, the flow of T₃ diffusing from the cell membrane to the nucleus is increased by T₃(T₄), which represents T₃ generated locally from T₄ via DIO2. By contrast, the DIO3 pathway decreases the flow of T₃ to the nucleus by terminally inactivating T₃ to T₂ and T₄ to rT₃ (rT₃, T₂). DIO2 generates T₃ in a cell compartment adjacent to the nucleus. By contrast, DIO3 largely resides in the periphery of the cell in the plasma membrane and early endosomes. Once inside cells, T₃ can diffuse to the nucleus to modulate gene expression. Abbreviations: DIO, iodothyronine deiodinase; rT₃, reverse tri-iodothyronine; T₂, di-iodothyronine; T₃, tri-iodothyronine; T₄, tetra-iodothyronine. Courtesy of BiancoLab.org.

Figure 2

T₄-induced DIO2 ubiquitination in thyroid hormone homeostasis. In response to thyroid hormone signals from the periphery and DIO2-expressing tanycytes, hypophysiotropic TRH-expressing neurons release TRH into the portal blood. TRH is transported to the anterior pituitary gland where TSH is secreted and stimulates the thyroid gland to produce and secrete T₄ and T₃. Hypothalamic T₃ is generated locally by tanycytes and enters the systemic circulation. T₃ can also be generated in the periphery via DIO1. In most peripheral tissues, exposure to T₄ accelerates inactivation of DIO2 (UbDIO2) and UbDIO2 targeting to the proteasomal system; however, UbDIO2 can be reactivated and rescued fromproteasomal destruction by deubiquitination. Peripheral deiodination is very sensitive to T₄-induced DIO2 ubiquitination: a mild increase in the serum T₄:T₃ ratio favours DIO2 inactivation and decreases fractional T₄-to-T₃ conversion and peripheral T₃ production. However in the hypothalamus, DIO2 is less susceptible to T₄-induced ubiquitination than in other tissues. Thus, T₄ signalling via DIO2-mediated T₃ production is very effective in the hypothalamus, whereas T₃ production via DIO2 is easily inhibited in the periphery. Abbreviations: DIO, iodothyronine deiodinase; T₂, di-iodothyronine; T₃, tri-iodothyronine; T₄, tetra-iodothyronine; TRH, TSH-releasing hormone; UbDIO2, ubiquitinated DIO2. Permission obtained from American Society for Clinical Investigation © Werneck de Castro, J. P. et al. J. Clin. Invest. 125, 769–781 (2015).