Curcio-Morelli Cyntia, Zavacki Ann Marie, Christofollete Marcelo, Gereben Balazs, de Freitas Beatriz C G, Harney John W, Li Zaibo, Wu Guan, Bianco Antonio C
Division of Endocrinology, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115, USA.
J Clin Invest. 2003 Jul;112(2):189-96. doi: 10.1172/JCI18348.
The type 2 iodothyronine deiodinase (D2) is an integral membrane ER-resident selenoenzyme that activates the pro-hormone thyroxine (T4) and supplies most of the 3,5,3'-triiodothyronine (T3) that is essential for brain development. D2 is inactivated by selective conjugation to ubiquitin, a process accelerated by T4 catalysis and essential for the maintenance of T3 homeostasis. A yeast two-hybrid screen of a human-brain library with D2 as bait identified von Hippel-Lindau protein-interacting deubiquitinating enzyme-1 (VDU1). D2 interaction with VDU1 and VDU2, a closely related deubiquitinase, was confirmed in mammalian cells. Both VDU proteins colocalize with D2 in the ER, and their coexpression prolongs D2 half-life and activity by D2 deubiquitination. VDU1, but not VDU2, is markedly increased in brown adipocytes by norepinephrine or cold exposure, further amplifying the increase in D2 activity that results from catecholamine-stimulated de novo synthesis. Thus, deubiquitination regulates the supply of active thyroid hormone to brown adipocytes and other D2-expressing cells.
2型碘甲状腺原氨酸脱碘酶（D2）是一种驻留在内质网的整合膜硒酶，可激活前体激素甲状腺素（T4），并提供对大脑发育至关重要的大部分3,5,3'-三碘甲状腺原氨酸（T3）。D2通过与泛素选择性结合而失活，这一过程由T4催化加速，对维持T3稳态至关重要。以D2为诱饵对人脑文库进行酵母双杂交筛选，鉴定出了与冯·希佩尔-林道蛋白相互作用的去泛素化酶-1（VDU1）。在哺乳动物细胞中证实了D2与VDU1以及与之密切相关的去泛素化酶VDU2之间的相互作用。两种VDU蛋白均与D2在内质网中共定位，并且它们的共表达通过D2去泛素化延长了D2的半衰期并增强了其活性。去甲肾上腺素或冷暴露可使棕色脂肪细胞中的VDU1显著增加，而VDU2则无此变化，这进一步放大了儿茶酚胺刺激的从头合成所导致的D2活性增加。因此，去泛素化调节了棕色脂肪细胞和其他表达D2的细胞中活性甲状腺激素的供应。
