Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain
Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain
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DOI：
10.1172/jci123176
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发表时间：
2019-01-02
影响因子：
15.9
通讯作者：
Bianco, Antonio C.
中科院分区：
文献类型：
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作者：
Jo, Sungro;Fonseca, Tatiana L.;Bianco, Antonio C.
左旋甲状腺素 (LT4) 是一种甲状腺激素，用于治疗甲状腺功能减退症。在大脑中，T4 通过 2 型脱碘酶 (D2) 转化为活性形式 T3。因此，有趣的是，当 LT4 疗法中添加碘塞罗宁 (LT3) 时，D2 基因 (DIO2) 中 Thr92Ala 多态性的携带者表现出临床改善。在这里，我们报道 D2 是 ER 高尔基体中间室 (ERGIC) 囊泡中的货物蛋白，在 ER 和高尔基体之间循环。 Thr92 替换为 Ala (Ala92-D2) 会引起 ER 应激并激活未折叠蛋白反应 (UPR)。 Ala92-D2 在反式高尔基体中积累并产生较少的 T3，通过化学分子伴侣 4-苯基丁酸 (4-PBA) 消除 ER 应激可恢复 T3。携带 Ala92-Dio2 多态性的小鼠在不同的大脑区域表现出 UPR 和甲状腺功能减退症。老鼠避免了体力活动，睡得更多，并且需要更多的时间来记住物体。用 LT3 增强大脑中的 T3 信号传导可以改善认知能力，而用 4-PBA 恢复蛋白质稳态则可以消除 Ala92-Dio2 表型。相比之下，原发性甲状腺功能减退症加剧了 Ala92-Dio2 表型，对 LT4 治疗仅有部分反应。细胞蛋白质稳态的破坏和 Ala92-D2 活性的降低可能解释了 Thr92Ala-DIO2 携带者 LT4 治疗失败的原因。
Levothyroxine (LT4) is a form of thyroid hormone used to treat hypothyroidism. In the brain, T4 is converted to the active form T3 by type 2 deiodinase (D2). Thus, it is intriguing that carriers of the Thr92Ala polymorphism in the D2 gene (DIO2) exhibit clinical improvement when liothyronine (LT3) is added to LT4 therapy. Here, we report that D2 is a cargo protein in ER Golgi intermediary compartment (ERGIC) vesicles, recycling between ER and Golgi. The Thr92-to-Ala substitution (Ala92-D2) caused ER stress and activated the unfolded protein response (UPR). Ala92-D2 accumulated in the trans-Golgi and generated less T3, which was restored by eliminating ER stress with the chemical chaperone 4-phenyl butyric acid (4-PBA). An Ala92-Dio2 polymorphism-carrying mouse exhibited UPR and hypothyroidism in distinct brain areas. The mouse refrained from physical activity, slept more, and required additional time to memorize objects. Enhancing T3 signaling in the brain with LT3 improved cognition, whereas restoring proteostasis with 4-PBA eliminated the Ala92-Dio2 phenotype. In contrast, primary hypothyroidism intensified the Ala92-Dio2 phenotype, with only partial response to LT4 therapy. Disruption of cellular proteostasis and reduced Ala92-D2 activity may explain the failure of LT4 therapy in carriers of Thr92Ala-DIO2.