Division of Endocrinology, Diabetes and Metabolism, University of Miami, Miller School of Medicine, Miami, FL 33136, United States.
Int J Biochem Cell Biol. 2011 Oct;43(10):1432-41. doi: 10.1016/j.biocel.2011.05.016. Epub 2011 Jun 12.
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.
甲状腺激素的作用可以通过脱碘酶家族的酶的控制作用，以细胞特异性的方式进行定制，这些酶是具有二硫键还原酶折叠的同二聚体硒蛋白。虽然 II 型脱碘酶（D2）通过将前激素甲状腺素（T4）激活为生物活性 T3 分子来启动甲状腺激素信号，但 III 型脱碘酶（D3）通过催化 T4 和 T3 分子的失活来终止甲状腺激素作用。脱碘酶通过影响细胞内 T3 水平从而在细胞特异性基础上影响基因表达，在甲状腺激素动态平衡、发育、生长和代谢控制中发挥作用。虽然 Dio2 和 Dio3 都受到转录调控，但 D2 的泛素化是一种控制 D2 活性和细胞内 T3 产生的开关机制。刺猬诱导的 WSB-1 和酵母 Doa10 哺乳动物同源物 TEB4 是两种 E3 连接酶，通过泛素化使 D2 失活。失活涉及 D2:D2 二聚体的破坏，并且可以通过两种泛素特异性蛋白酶 USP20 和 USP33 逆转，恢复催化活性和 T3 产生。控制 D2 活性的基于泛素的开关机制说明了不同类型的细胞如何微调甲状腺激素信号，使 D2 成为药理学干预的合适靶标。本文综述了 D2 调节的细胞和分子方面以及目前的 D2 介导的甲状腺激素信号模型。
