Zhang Xiaohan, Young Crystal, Liao Xiao-Hui, Refetoff Samuel, Mutchler Stephanie M, Brodsky Jeffrey L, Buck Teresa M, Arvan Peter
Division of Metabolism, Endocrinology & Diabetes, and.
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
JCI Insight. 2025 Sep 9;10(17). doi: 10.1172/jci.insight.191837.
Intracellular trafficking of secretory and membrane proteins from the endoplasmic reticulum (ER) to the cell surface, via the secretory pathway, is crucial to the differentiated function of epithelial tissues. In the thyroid gland, a prerequisite for such trafficking is proper protein folding in the ER, assisted by an array of ER molecular chaperones. One of the most abundant of these chaperones, Glucose-Regulated-Protein-170 (GRP170, encoded by Hyou1), is a noncanonical hsp70-like family member. Thyroid follicular epithelial cells abundantly express GRP170, but the role of this abundant ER chaperone in thyrocytes remains unknown. Here, we have examined the effect of inducible Pax8-specific (thyroid and kidney) deficiency of GRP170 in mice, in parallel with siRNA-treated PCCL3 (rat) thyrocytes for knockdown of GRP170. Thyrocyte-specific loss of GRP170 in vivo triggers primary hypothyroidism with a deficient thyroidal response to Thyroid-Stimulating Hormone (TSH). In addition, knockdown of GRP170 in PCCL3 thyrocytes inhibits the folding and forward trafficking of TSH receptors to the cell surface. Taken together, our findings suggest that GRP170 contributes to the conformational maturation of TSH receptors and thyroid gland responsiveness to TSH, which is required for proper regulation of thyroid hormone synthesis.
通过分泌途径，将分泌性和膜蛋白从内质网（ER）转运至细胞表面的细胞内运输，对于上皮组织的分化功能至关重要。在甲状腺中，这种运输的一个先决条件是在内质网中由一系列内质网分子伴侣辅助进行适当的蛋白质折叠。这些伴侣中最丰富的一种，葡萄糖调节蛋白170（GRP170，由Hyou1编码），是一种非典型的hsp70样家族成员。甲状腺滤泡上皮细胞大量表达GRP170，但这种丰富的内质网伴侣在甲状腺细胞中的作用仍然未知。在这里，我们研究了在小鼠中诱导性Pax8特异性（甲状腺和肾脏）GRP170缺陷的影响，并与用siRNA处理的PCCL3（大鼠）甲状腺细胞敲低GRP170进行了平行研究。体内甲状腺细胞特异性GRP170缺失引发原发性甲状腺功能减退，甲状腺对促甲状腺激素（TSH）的反应不足。此外，敲低PCCL3甲状腺细胞中的GRP170会抑制促甲状腺激素受体向细胞表面的折叠和正向运输。综上所述，我们的研究结果表明，GRP170有助于促甲状腺激素受体的构象成熟以及甲状腺对促甲状腺激素的反应性，这是甲状腺激素合成正常调节所必需的。
