Department of Life Sciences and Chemistry, Jacobs University Bremen, Bremen, Germany.
Present address of JS is Department of Internal Medicine III, Cardiology, Angiology and Respiratory Medicine, Universitätsklinikum Heidelberg, Heidelberg, Germany.
Exp Clin Endocrinol Diabetes. 2020 Jun;128(6-07):437-445. doi: 10.1055/a-1080-2969. Epub 2020 Feb 19.
This mini-review asks how self-regulation of the thyroid gland is realized at the cellular and molecular levels by canonical and non-canonical means. Canonical pathways of thyroid regulation comprise thyroid stimulating hormone-triggered receptor signaling. As part of non-canonical regulation, we hypothesized an interplay between protease-mediated thyroglobulin processing and thyroid hormone release into the circulation by means of thyroid hormone transporters like Mct8. We proposed a sensing mechanism by different thyroid hormone transporters, present in specific subcellular locations of thyroid epithelial cells, selectively monitoring individual steps of thyroglobulin processing, and thus, the cellular thyroid hormone status. Indeed, we found that proteases and thyroid hormone transporters are functionally inter-connected, however, in a counter-intuitive manner fostering self-thyrotoxicity in particular in Mct8- and/or Mct10-deficient mice. Furthermore, the possible role of the G protein-coupled receptor Taar1 is discussed, because we detected Taar1 at cilia of the apical plasma membrane of thyrocytes and . Eventually, through pheno-typing Taar1-deficient mice, we identified a co-regulatory role of Taar1 and the thyroid stimulating hormone receptors. Recently, we showed that inhibition of thyroglobulin-processing enzymes results in disappearance of cilia from the apical pole of thyrocytes, while Taar1 is re-located to the endoplasmic reticulum. This pathway features a connection between thyrotropin-stimulated secretion of proteases into the thyroid follicle lumen and substrate-mediated self-assisted control of initially peri-cellular thyroglobulin processing, before its reinternalization by endocytosis, followed by extensive endo-lysosomal liberation of thyroid hormones, which are then released from thyroid follicles by means of thyroid hormone transporters.
这篇迷你综述探讨了经典和非经典途径如何在细胞和分子水平上实现甲状腺的自我调节。甲状腺调节的经典途径包括促甲状腺激素触发的受体信号转导。作为非经典调节的一部分，我们假设蛋白酶介导的甲状腺球蛋白处理与甲状腺激素通过 Mct8 等甲状腺激素转运体释放到循环中的相互作用。我们提出了一种由不同的甲状腺激素转运体在甲状腺上皮细胞的特定亚细胞位置中存在的感应机制，该机制选择性地监测甲状腺球蛋白处理的各个步骤，从而监测细胞内的甲状腺激素状态。事实上，我们发现蛋白酶和甲状腺激素转运体在功能上相互连接，但以一种反直觉的方式促进了自身毒性，特别是在 Mct8 和/或 Mct10 缺陷小鼠中。此外，还讨论了 G 蛋白偶联受体 Taar1 的可能作用，因为我们在甲状腺细胞的顶质膜的纤毛上检测到了 Taar1 。最终，通过对 Taar1 缺陷小鼠进行表型分析，我们确定了 Taar1 和促甲状腺激素受体的共同调节作用。最近，我们表明，抑制甲状腺球蛋白处理酶会导致甲状腺细胞顶极纤毛从顶极消失，而 Taar1 被重新定位到内质网。该途径特征在于促甲状腺激素刺激的蛋白酶进入甲状腺滤泡腔的分泌与底物介导的最初细胞周甲状腺球蛋白处理的自我辅助控制之间的连接，然后通过内吞作用将其再内化，随后在内溶酶体中广泛释放甲状腺激素，然后通过甲状腺激素转运体从甲状腺滤泡中释放。
