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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Preferential megalin-mediated transcytosis of low-hormonogenic thyroglobulin: A control mechanism for thyroid hormone release
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Preferential megalin-mediated transcytosis of low-hormonogenic thyroglobulin: A control mechanism for thyroid hormone release

机译：低激素甲状腺球蛋白的优先性巨蛋白介导的胞吞作用：甲状腺激素释放的控制机制

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Hormone secretion by thyrocytes occurs by fluid phase uptake and lysosomal degradation of the prohormone thyroglobulin (Tg). However, some Tg internalized by megalin bypasses lysosomes and is transcytosed across cells and released into the bloodstream. Because the hormone content of Tg is variable, we investigated whether this affects transcytosis. We found that rat Tg with a low hormone content [low-hormonogenic rat Tg (low-horm-rTg)] is transcytosed by megalin across thyroid FRTL-5 cells to a greater extent than rat Tg with a high hormone content [hormonogenic rat Tg (horm-rTg)]. In immunoprecipitation experiments, the Tg sequence Arg-2489-Lys-2503 (required for binding to megalin and heparan sulfate proteoglycans) was found to be more exposed in low-horm-rTg, which accounted for its preferential transcytosis. Thus, removal of surface heparan sulfate proteoglycans from FRTL-5 cells or blocking of 2489-2503 reduced transcytosis of low-horm-rTg to a greater extent than that of horm-rTg. Preferential transcytosis of low-horm-rTg affected hormone release. Thus, the increase in hormone release from horm-rTg in FRTL-5 cells determined by megalin blocking (due to reduced transcytosis and enhanced Tg degradation) was rescued by low-horm-rTg, suggesting that megalin is required for effective hormone release. This finding was confirmed in a small number of megalin-deficient mice, which had serological features resembling mild hypothyroidism. Reduced hormone formation within Tg in vivo, due to treatment of rats with aminotriazole or of patients with Graves' disease with methimazole, resulted in increased Tg transcytosis via megalin, in confirmation of results with FRTL-5 cells. Our study points to a major role of megalin in thyroid homeostasis with possible implications in thyroid diseases.
机译：甲状腺细胞的激素分泌是通过前激素甲状腺球蛋白（Tg）的液相吸收和溶酶体降解而发生的。但是，一些被巨蛋白内在化的Tg绕过了溶酶体，并跨细胞转运并释放到血液中。由于Tg的激素含量是可变的，因此我们研究了这是否影响转胞吞作用。我们发现，具有低激素含量的大鼠Tg [低激素血症大鼠Tg（low-horm-rTg）]比具有高激素含量的大鼠Tg [巨激素大鼠Tg]被巨蛋白跨甲状腺FRTL-5细胞转运（horm-rTg）]。在免疫沉淀实验中，发现Tg序列Arg-2489-Lys-2503（与巨蛋白和硫酸乙酰肝素蛋白聚糖结合需要）在低激素rTg中更暴露，这说明其优先转座。因此，从FRTL-5细胞中去除表面硫酸乙酰肝素蛋白聚糖或阻断2489-2503降低了低激素rTg的转胞作用，其程度比激素rTg更大。低激素-rTg的优先转胞作用影响激素释放。因此，通过低激素-rTg可以挽救因巨蛋白阻滞而决定的FRTL-5细胞从激素-rTg释放的激素的增加（由于减少的胞吞作用和增强的Tg降解），这表明有效的激素释放需要巨蛋白。少数患有巨蛋白缺乏症的小鼠证实了这一发现，这些小鼠的血清学特征类似于轻度甲状腺功能减退症。 FRTL-5细胞的结果证实，由于用氨基三唑治疗大鼠或用甲巯咪唑治疗患有Graves病的患者，体内Tg内的激素形成减少，导致经由megalin的Tg胞吞作用增加，这证实了FRTL-5细胞的结果。我们的研究指出了巨蛋白在甲状腺稳态中的主要作用，可能对甲状腺疾病具有潜在的影响。

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