Type 2 deiodinase at the crossroads of thyroid hormone action.
Type 2 deiodinase at the crossroads of thyroid hormone action.
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DOI：
10.1016/j.biocel.2011.05.016
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发表时间：
2011-10
影响因子：
4
通讯作者：
Bianco, Antonio C.
中科院分区：
文献类型：
--
作者：
Arrojo e Drigo, Rafael;Bianco, Antonio C.
甲状腺激素作用可以通过脱碘酶组的受控作用以细胞特异性方式定制，脱碘酶组是含硒蛋白的同型二聚体硫氧还蛋白折叠。II型脱碘酶（D2）通过将激素原甲状腺素（T4）活化为具有生物活性的T3分子来启动甲状腺激素信号传导，而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T3的细胞内水平，从而在细胞特异性基础上影响基因表达，在甲状腺激素稳态、发育、生长和代谢控制中发挥作用。尽管Dio 2和Dio 3都是转录调节的，但D2的泛素化是控制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Doa 10哺乳动物直系同源物TEB 4是两种E3连接酶，通过泛素化修饰D2。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USP 20和USP 33逆转，从而挽救催化活性和T3产生。控制D2活性的基于泛素的开关机制说明了不同细胞类型如何微调甲状腺激素信号，使D2成为药物干预的合适靶点。本文综述了D2调节的细胞和分子方面以及目前D2介导的甲状腺激素信号转导模型。
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.
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