Abstract
Cathepsin K-mediated thyroglobulin proteolysis contributes to thyroid hormone (TH) liberation, while TH transporters like Mct8 and Mct10 ensure TH release from thyroid follicles into the blood circulation. Thus, thyroid stimulating hormone (TSH) released upon TH demand binds to TSH receptors of thyrocytes, where it triggers Gαq-mediated short-term effects like cathepsin-mediated thyroglobulin utilization, and Gαs-mediated long-term signaling responses like thyroglobulin biosynthesis and thyrocyte proliferation. As reported recently, mice lacking Mct8 and Mct10 on a cathepsin K-deficient background exhibit excessive thyroglobulin proteolysis hinting towards altered TSH receptor signaling. Indeed, a combination of canonical basolateral and non-canonical vesicular TSH receptor localization was observed in Ctsk−/−/Mct8−/y/Mct10−/− mice, which implies prolonged Gαs-mediated signaling since endo-lysosomal down-regulation of the TSH receptor was not detected. Inspection of single knockout genotypes revealed that the TSH receptor localizes basolaterally in Ctsk−/− and Mct8−/y mice, whereas its localization is restricted to vesicles in Mct10−/− thyrocytes. The additional lack of cathepsin K reverses this effect, because Ctsk−/−/Mct10−/− mice display TSH receptors basolaterally, thereby indicating that cathepsin K and Mct10 contribute to TSH receptor homeostasis by maintaining its canonical localization in thyrocytes. Moreover, Mct10−/− mice displayed reduced numbers of dead thyrocytes, while their thyroid gland morphology was comparable to wild-type controls. In contrast, Mct8−/y, Mct8−/y/Mct10−/−, and Ctsk−/−/Mct8−/y/Mct10−/− mice showed enlarged thyroid follicles and increased cell death, indicating that Mct8 deficiency results in altered thyroid morphology. We conclude that vesicular TSH receptor localization does not result in different thyroid tissue architecture; however, Mct10 deficiency possibly modulates TSH receptor signaling for regulating thyrocyte survival.
Highlights
The thyroid gland functions to supply the thyroid hormones (TH) triiodothyronine (T3) and thyroxine (T4) to almost all tissues of the body, a process that is enabled by proteolytic cleavage of the prohormone thyroglobulin (Tg) by cathepsins B, D, K, L, andS [1]
Since Tg biosynthesis is regulated via Gαs, while Tg proteolysis is mediated by Gαq, we suggest that intrathyroidal thyroid stimulating hormone (TSH) receptor signaling might be altered in TH transporter deficiencies, on a cathepsin K-deficient background, resulting in altered thyroid functional phenotypes
We report in the present study that serum TSH
Summary
The thyroid gland functions to supply the thyroid hormones (TH) triiodothyronine (T3) and thyroxine (T4) to almost all tissues of the body, a process that is enabled by proteolytic cleavage of the prohormone thyroglobulin (Tg) by cathepsins B, D, K, L, andS [1]. The classical pathway of thyroid gland regulation via the hypothalamus–pituitary–thyroid (HPT) axis encompasses triggering thyroid stimulating hormone (TSH) receptor signaling to thyrocytes by binding of its ligand TSH, a glycoprotein hormone of the pituitary, that itself is regulated by negative feedback upon TH demand [4,5]. The TSH receptor belongs to the G-protein coupled receptors (GPCR), whereby TSH-induced signaling regulates Tg turnover through Gαs -mediated long-term and Gαq -mediated short-term responses that respectively balance the repetitive cycles of Tg biosynthesis and Tg proteolysis for TH liberation [3]. We have reported that mice lacking Mct and Mct on a cathepsin Kdeficient background exhibit autophagy-induced excessive cathepsin-mediated Tg proteolysis [6]. The resulting enhanced intrathyroidal TH accumulation, due to the lack of exporting TH transporters, leads to self-toxicity in thyrocytes of Ctsk−/− /Mct8−/y /Mct10−/−
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