Arrojo E Drigo Rafael, Fonseca Tatiana L, Werneck-de-Castro Joao Pedro Saar, Bianco Antonio C
Division of Endocrinology, Diabetes and Metabolism, University of Miami, Miller School of Medicine, Miami, FL, USA.
Biochim Biophys Acta. 2013 Jul;1830(7):3956-64. doi: 10.1016/j.bbagen.2012.08.019. Epub 2012 Aug 29.
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.
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.
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.
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.
甲状腺激素信号传导对于脊椎动物的发育、生长和代谢控制至关重要。尽管血清甲状腺激素浓度显著稳定，但脱碘酶通过控制甲状腺激素的激活和失活，以时间和细胞特异性的方式调节甲状腺激素信号传导。
本综述涵盖了D2生物学的最新进展，D2是碘甲腺原氨酸脱碘酶家族的成员，属于含硫氧还蛋白折叠的硒酶，可在时间和细胞特异性方式下修饰甲状腺激素信号传导。
D2催化的T3生成增加甲状腺激素信号传导，而阻断D2活性或破坏Dio2基因会导致局部甲状腺功能减退状态。D2的表达受不同的发育、代谢或环境信号调节，如刺猬通路、肾上腺素能和TGR5激活的cAMP通路，受黄酮醇等外源性分子以及内质网应激调节，内质网应激通过eIF2a介导的机制特异性降低D2的从头合成。因此，D2在重要的生理过程中起核心作用，如确定发育组织和成年大脑中的T3含量，以及促进棕色脂肪组织中的适应性产热。值得注意的是，D2在垂体和下丘脑水平的T4介导的负反馈中至关重要，由此T4分别抑制TSH和TRH表达。值得注意的是，泛素化是控制D2活性的主要步骤，由此T4结合和/或T4催化通过E3泛素连接酶WSB-1和/或TEB4介导的泛素化触发D2失活。泛素化的D2可靶向蛋白酶体降解或通过去泛素化重新激活，去泛素化过程由去泛素酶USP20/33介导，在适应性产热中很重要。
在此，我们综述了对D2生物学理解的最新进展，重点关注调节其表达的机制及其在代谢相关组织中的生物学意义。本文是名为甲状腺激素信号传导的特刊的一部分。
