The Amino Acid Transporter Mct10/Tat1 Is Important to Maintain the TSH Receptor at Its Canonical Basolateral Localization and Assures Regular Turnover of Thyroid Follicle Cells in Male Mice
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 thyr...
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2021-05-01
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| author | Vaishnavi Venugopalan Alaa Al-Hashimi Jonas Weber Maren Rehders Maria Qatato Eva K. Wirth Ulrich Schweizer Heike Heuer François Verrey Klaudia Brix |
| author_facet | Vaishnavi Venugopalan Alaa Al-Hashimi Jonas Weber Maren Rehders Maria Qatato Eva K. Wirth Ulrich Schweizer Heike Heuer François Verrey Klaudia Brix |
| author_sort | Vaishnavi Venugopalan |
| collection | DOAJ |
| description | 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 Gα<sub>q</sub>-mediated short-term effects like cathepsin-mediated thyroglobulin utilization, and Gα<sub>s</sub>-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 <i>Ctsk</i><sup>−/−</sup>/<i>Mct8</i><sup>−/y</sup>/<i>Mct10</i><sup>−/−</sup> mice, which implies prolonged Gα<sub>s</sub>-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 <i>Ctsk</i><sup>−/−</sup> and <i>Mct8</i><sup>−/y</sup> mice, whereas its localization is restricted to vesicles in <i>Mct10</i><sup>−/−</sup> thyrocytes. The additional lack of cathepsin K reverses this effect, because <i>Ctsk</i><sup>−/−</sup>/<i>Mct10</i><sup>−/−</sup> 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, <i>Mct10</i><sup>−/−</sup> mice displayed reduced numbers of dead thyrocytes, while their thyroid gland morphology was comparable to wild-type controls. In contrast, <i>Mct8</i><sup>−/y</sup>, <i>Mct8</i><sup>−/y</sup>/<i>Mct10</i><sup>−/−</sup>, and <i>Ctsk</i><sup>−/−</sup>/<i>Mct8</i><sup>−/y</sup>/<i>Mct10</i><sup>−/−</sup> 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. |
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| spelling | doaj.art-4cce63c801f045b8aea1b66b775b36a62023-11-21T21:48:12ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-012211577610.3390/ijms22115776The Amino Acid Transporter Mct10/Tat1 Is Important to Maintain the TSH Receptor at Its Canonical Basolateral Localization and Assures Regular Turnover of Thyroid Follicle Cells in Male MiceVaishnavi Venugopalan0Alaa Al-Hashimi1Jonas Weber2Maren Rehders3Maria Qatato4Eva K. Wirth5Ulrich Schweizer6Heike Heuer7François Verrey8Klaudia Brix9Department of Life Sciences and Chemistry, Focus Area HEALTH, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, GermanyDepartment of Life Sciences and Chemistry, Focus Area HEALTH, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, GermanyDepartment of Life Sciences and Chemistry, Focus Area HEALTH, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, GermanyDepartment of Life Sciences and Chemistry, Focus Area HEALTH, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, GermanyDepartment of Life Sciences and Chemistry, Focus Area HEALTH, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, GermanyBerlin Institute of Health, Department of Endocrinology and Metabolism, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Hessische Str. 3-4, D-10115 Berlin, GermanyInstitut für Biochemie und Molekularbiologie, Universitätsklinikum Bonn, Nußallee 11, D-53115 Bonn, GermanyDepartment of Endocrinology, Diabetes and Metabolism, University of Duisburg-Essen, Universitätsklinikum Essen, Hufelandstr. 55, D-45147 Essen, GermanyPhysiologisches Institut, Universität Zürich, Winterthurerstr. 190, CH-8057 Zürich, SwitzerlandDepartment of Life Sciences and Chemistry, Focus Area HEALTH, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, GermanyCathepsin 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 Gα<sub>q</sub>-mediated short-term effects like cathepsin-mediated thyroglobulin utilization, and Gα<sub>s</sub>-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 <i>Ctsk</i><sup>−/−</sup>/<i>Mct8</i><sup>−/y</sup>/<i>Mct10</i><sup>−/−</sup> mice, which implies prolonged Gα<sub>s</sub>-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 <i>Ctsk</i><sup>−/−</sup> and <i>Mct8</i><sup>−/y</sup> mice, whereas its localization is restricted to vesicles in <i>Mct10</i><sup>−/−</sup> thyrocytes. The additional lack of cathepsin K reverses this effect, because <i>Ctsk</i><sup>−/−</sup>/<i>Mct10</i><sup>−/−</sup> 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, <i>Mct10</i><sup>−/−</sup> mice displayed reduced numbers of dead thyrocytes, while their thyroid gland morphology was comparable to wild-type controls. In contrast, <i>Mct8</i><sup>−/y</sup>, <i>Mct8</i><sup>−/y</sup>/<i>Mct10</i><sup>−/−</sup>, and <i>Ctsk</i><sup>−/−</sup>/<i>Mct8</i><sup>−/y</sup>/<i>Mct10</i><sup>−/−</sup> 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.https://www.mdpi.com/1422-0067/22/11/5776monocarboxylate transporter 10/Scl16a10thyroid gland architecturethyrocyte survivalTSH receptor signaling |
| spellingShingle | Vaishnavi Venugopalan Alaa Al-Hashimi Jonas Weber Maren Rehders Maria Qatato Eva K. Wirth Ulrich Schweizer Heike Heuer François Verrey Klaudia Brix The Amino Acid Transporter Mct10/Tat1 Is Important to Maintain the TSH Receptor at Its Canonical Basolateral Localization and Assures Regular Turnover of Thyroid Follicle Cells in Male Mice International Journal of Molecular Sciences monocarboxylate transporter 10/Scl16a10 thyroid gland architecture thyrocyte survival TSH receptor signaling |
| title | The Amino Acid Transporter Mct10/Tat1 Is Important to Maintain the TSH Receptor at Its Canonical Basolateral Localization and Assures Regular Turnover of Thyroid Follicle Cells in Male Mice |
| title_full | The Amino Acid Transporter Mct10/Tat1 Is Important to Maintain the TSH Receptor at Its Canonical Basolateral Localization and Assures Regular Turnover of Thyroid Follicle Cells in Male Mice |
| title_fullStr | The Amino Acid Transporter Mct10/Tat1 Is Important to Maintain the TSH Receptor at Its Canonical Basolateral Localization and Assures Regular Turnover of Thyroid Follicle Cells in Male Mice |
| title_full_unstemmed | The Amino Acid Transporter Mct10/Tat1 Is Important to Maintain the TSH Receptor at Its Canonical Basolateral Localization and Assures Regular Turnover of Thyroid Follicle Cells in Male Mice |
| title_short | The Amino Acid Transporter Mct10/Tat1 Is Important to Maintain the TSH Receptor at Its Canonical Basolateral Localization and Assures Regular Turnover of Thyroid Follicle Cells in Male Mice |
| title_sort | amino acid transporter mct10 tat1 is important to maintain the tsh receptor at its canonical basolateral localization and assures regular turnover of thyroid follicle cells in male mice |
| topic | monocarboxylate transporter 10/Scl16a10 thyroid gland architecture thyrocyte survival TSH receptor signaling |
| url | https://www.mdpi.com/1422-0067/22/11/5776 |
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