{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:02:17Z","timestamp":1760234537269,"version":"build-2065373602"},"reference-count":41,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T00:00:00Z","timestamp":1622160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["BR 1308\/11-1, 11-2","SCHW 914\/6-1","HE 3418\/7-1, 7-2"],"award-info":[{"award-number":["BR 1308\/11-1, 11-2","SCHW 914\/6-1","HE 3418\/7-1, 7-2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002839","name":"Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin","doi-asserted-by":"publisher","award":["Rahel-Hirsch stipend to E.K.W."],"award-info":[{"award-number":["Rahel-Hirsch stipend to E.K.W."]}],"id":[{"id":"10.13039\/501100002839","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["31_166430\/1 to F.V."],"award-info":[{"award-number":["31_166430\/1 to F.V."]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 G\u03b1q-mediated short-term effects like cathepsin-mediated thyroglobulin utilization, and G\u03b1s-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\u2212\/\u2212\/Mct8\u2212\/y\/Mct10\u2212\/\u2212 mice, which implies prolonged G\u03b1s-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\u2212\/\u2212 and Mct8\u2212\/y mice, whereas its localization is restricted to vesicles in Mct10\u2212\/\u2212 thyrocytes. The additional lack of cathepsin K reverses this effect, because Ctsk\u2212\/\u2212\/Mct10\u2212\/\u2212 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\u2212\/\u2212 mice displayed reduced numbers of dead thyrocytes, while their thyroid gland morphology was comparable to wild-type controls. In contrast, Mct8\u2212\/y, Mct8\u2212\/y\/Mct10\u2212\/\u2212, and Ctsk\u2212\/\u2212\/Mct8\u2212\/y\/Mct10\u2212\/\u2212 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.<\/jats:p>","DOI":"10.3390\/ijms22115776","type":"journal-article","created":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T11:33:20Z","timestamp":1622201600000},"page":"5776","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"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"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6772-6787","authenticated-orcid":false,"given":"Vaishnavi","family":"Venugopalan","sequence":"first","affiliation":[{"name":"Department of Life Sciences and Chemistry, Focus Area HEALTH, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alaa","family":"Al-Hashimi","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Chemistry, Focus Area HEALTH, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonas","family":"Weber","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Chemistry, Focus Area HEALTH, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maren","family":"Rehders","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Chemistry, Focus Area HEALTH, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Qatato","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Chemistry, Focus Area HEALTH, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0491-9941","authenticated-orcid":false,"given":"Eva K.","family":"Wirth","sequence":"additional","affiliation":[{"name":"Berlin Institute of Health, Department of Endocrinology and Metabolism, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin and DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Hessische Str. 3-4, D-10115 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrich","family":"Schweizer","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Biochemie und Molekularbiologie, Universit\u00e4tsklinikum Bonn, Nu\u00dfallee 11, D-53115 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heike","family":"Heuer","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism, University of Duisburg-Essen, Universit\u00e4tsklinikum Essen, Hufelandstr. 55, D-45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fran\u00e7ois","family":"Verrey","sequence":"additional","affiliation":[{"name":"Physiologisches Institut, Universit\u00e4t Z\u00fcrich, Winterthurerstr. 190, CH-8057 Z\u00fcrich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4476-0357","authenticated-orcid":false,"given":"Klaudia","family":"Brix","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Chemistry, Focus Area HEALTH, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Luster, M., Duntas, L.H., and Wartofsky, L. (2019). Thyroglobulin Storage, Processing and Degradation for Thyroid Hormone Liberation. The Thyroid and Its Diseases, Springer International Publishing.","DOI":"10.1007\/978-3-319-72102-6"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1210\/endrev\/bnz008","article-title":"Thyroid Hormone Transporters","volume":"41","author":"Groeneweg","year":"2020","journal-title":"Endocr. Rev."},{"key":"ref_3","first-page":"437","article-title":"Auto-Regulation of the Thyroid Gland Beyond Classical Pathways","volume":"128","author":"Brix","year":"2020","journal-title":"Exp. Clin. Endocrinol. Diabetes Off. J. Ger. Soc. Endocrinol. Ger. Diabetes Assoc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"R197","DOI":"10.1530\/EJE-14-0285","article-title":"Beyond the fixed setpoint of the hypothalamus-pituitary-thyroid axis","volume":"171","author":"Fliers","year":"2014","journal-title":"Eur. J. Endocrinol."},{"key":"ref_5","first-page":"1387","article-title":"Hypothalamus-Pituitary-Thyroid Axis","volume":"6","author":"Chiamolera","year":"2016","journal-title":"Compr. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Venugopalan, V., Al-Hashimi, A., Rehders, M., Golchert, J., Reinecke, V., Homuth, G., V\u00f6lker, U., Manirajah, M., Touzani, A., and Weber, J. (2021). The Thyroid Hormone Transporter Mct8 Restricts Cathepsin-Mediated Thyroglobulin Processing in Male Mice through Thyroid Auto-Regulatory Mechanisms That Encompass Autophagy. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010462"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"221","DOI":"10.3389\/fphar.2018.00221","article-title":"Canonical TSH Regulation of Cathepsin-Mediated Thyroglobulin Processing in the Thyroid Gland of Male Mice Requires Taar1 Expression","volume":"9","author":"Qatato","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.ejcb.2017.02.002","article-title":"Interdependence of thyroglobulin processing and thyroid hormone export in the mouse thyroid gland","volume":"96","author":"Weber","year":"2017","journal-title":"Eur. J. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000431318","article-title":"Understanding the Healthy Thyroid State in 2015","volume":"4","author":"Brix","year":"2015","journal-title":"Eur. Thyroid J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1530\/EJE-11-0369","article-title":"Monocarboxylate transporter 8 deficiency: Altered thyroid morphology and persistent high triiodothyronine\/thyroxine ratio after thyroidectomy","volume":"165","author":"Wirth","year":"2011","journal-title":"Eur. J. Endocrinol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1210\/en.2013-1800","article-title":"Tissue-specific alterations in thyroid hormone homeostasis in combined Mct10 and Mct8 deficiency","volume":"155","author":"Mayerl","year":"2014","journal-title":"Endocrinology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2399","DOI":"10.1172\/JCI30380","article-title":"Thyrocyte-specific Gq\/G11 deficiency impairs thyroid function and prevents goiter development","volume":"117","author":"Kero","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1172\/JCI15990","article-title":"Thyroid functions of mouse cathepsins B, K, and L","volume":"111","author":"Friedrichs","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1007\/s10571-019-00765-6","article-title":"Function of Cathepsin K in the Central Nervous System of Male Mice is Independent of Its Role in the Thyroid Gland","volume":"40","author":"Dauth","year":"2020","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1172\/JCI28253","article-title":"Abnormal thyroid hormone metabolism in mice lacking the monocarboxylate transporter 8","volume":"117","author":"Trajkovic","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1159\/000339474","article-title":"Understanding the hypothalamus-pituitary-thyroid axis in mct8 deficiency","volume":"1","author":"Heuer","year":"2012","journal-title":"Eur. Thyroid J."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Calebiro, D., Nikolaev, V.O., Gagliani, M.C., de Filippis, T., Dees, C., Tacchetti, C., Persani, L., and Lohse, M.J. (2009). Persistent cAMP-Signals Triggered by Internalized G-Protein\u2013Coupled Receptors. PLoS Biol., 7.","DOI":"10.1371\/journal.pbio.1000172"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.tips.2010.02.002","article-title":"Signaling by internalized G-protein-coupled receptors","volume":"31","author":"Calebiro","year":"2010","journal-title":"Trends Pharm. Sci"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/s41467-017-00357-2","article-title":"Internalized TSH receptors en route to the TGN induce local Gs-protein signaling and gene transcription","volume":"8","author":"Godbole","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"45217","DOI":"10.1074\/jbc.M103727200","article-title":"Oligomerization of the human thyrotropin receptor: Fluorescent protein-tagged hTSHR reveals post-translational complexes","volume":"276","author":"Latif","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1172\/JCI0216234","article-title":"The TSH receptor reveals itself","volume":"110","author":"Davies","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1007\/s00018-017-2728-1","article-title":"Evidence of G-protein-coupled receptor and substrate transporter heteromerization at a single molecule level","volume":"75","author":"Fischer","year":"2018","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.1210\/endo.137.5.8612537","article-title":"Evidence for extracellularly acting cathepsins mediating thyroid hormone liberation in thyroid epithelial cells","volume":"137","author":"Brix","year":"1996","journal-title":"Endocrinology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1515\/BC.2002.081","article-title":"Thyroid stimulating hormone upregulates secretion of cathepsin B from thyroid epithelial cells","volume":"383","author":"Linke","year":"2002","journal-title":"Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1152\/physrev.1992.72.3.667","article-title":"Physiological and pathological regulation of thyroid cell proliferation and differentiation by thyrotropin and other factors","volume":"72","author":"Dumont","year":"1992","journal-title":"Physiol. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1242\/dev.145615","article-title":"Development of the thyroid gland","volume":"144","author":"Nilsson","year":"2017","journal-title":"Development (Camb. Engl.)"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4036","DOI":"10.1210\/en.2006-0390","article-title":"Tissue-specific thyroid hormone deprivation and excess in monocarboxylate transporter (mct) 8-deficient mice","volume":"147","author":"Dumitrescu","year":"2006","journal-title":"Endocrinology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"13733","DOI":"10.1016\/S0021-9258(17)36705-4","article-title":"The human thyrotropin receptor activates G-proteins Gs and Gq\/11","volume":"269","author":"Allgeier","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_29","first-page":"3687","article-title":"Occupancy of both sites on the thyrotropin (TSH) receptor dimer is necessary for phosphoinositide signaling","volume":"25","author":"Allen","year":"2011","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1210\/en.2008-0953","article-title":"Sortilin is a putative postendocytic receptor of thyroglobulin","volume":"150","author":"Botta","year":"2009","journal-title":"Endocrinology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/85224","article-title":"Thyrocytes\u2014Not innocent bystanders in autoimmune disease","volume":"2","author":"Giordano","year":"2001","journal-title":"Nat. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1136\/bmj.322.7301.1525","article-title":"The role of apoptosis in autoimmune thyroid disorders and thyroid cancer","volume":"322","author":"Lin","year":"2001","journal-title":"BMJ"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/nri750","article-title":"Autoimmune thyroid disease: New models of cell death in autoimmunity","volume":"2","author":"Stassi","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1089\/thy.2000.10.561","article-title":"Death of the autoimmune thyrocyte: Is it pushed or does it jump?","volume":"10","author":"Palazzo","year":"2000","journal-title":"Thyroid Off. J. Am. Thyroid Assoc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1530\/eje.0.1440561","article-title":"The role of Fas-mediated apoptosis in thyroid disease","volume":"144","author":"Andrikoula","year":"2001","journal-title":"Eur. J. Endocrinol."},{"key":"ref_36","first-page":"169","article-title":"The role of apoptosis in thyroid disease","volume":"93","author":"Tsatsoulis","year":"2002","journal-title":"Minerva Med."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"McQuin, C., Goodman, A., Chernyshev, V., Kamentsky, L., Cimini, B.A., Karhohs, K.W., Doan, M., Ding, L., Rafelski, S.M., and Thirstrup, D. (2018). CellProfiler 3.0: Next-generation image processing for biology. PLoS Biol., 16.","DOI":"10.1371\/journal.pbio.2005970"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1515\/bchm2.1979.360.2.1657","article-title":"A simple, versatile, sensitive and volume-independent method for quantitative protein determination which is independent of other external influences","volume":"360","author":"Neuhoff","year":"1979","journal-title":"Hoppe-Seyler\u2019s Z. Physiol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1089\/thy.2013.0041","article-title":"Impact of Metformin and compound C on NIS expression and iodine uptake in vitro and in vivo: A role for CRE in AMPK modulation of thyroid function","volume":"24","author":"Abdulrahman","year":"2014","journal-title":"Thyroid Off. J. Am. Thyroid Assoc."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/s41586-020-2928-y","article-title":"Feeding induces cholesterol biosynthesis via the mTORC1\u2013USP20\u2013HMGCR axis","volume":"588","author":"Lu","year":"2020","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Kunath, A., Weiner, J., Krause, K., Rehders, M., Pejkovska, A., Gericke, M., Biniossek, M.L., Dommel, S., Kern, M., and Ribas-Latre, A. (2021). Role of Kallikrein 7 in Body Weight and Fat Mass Regulation. Biomedicines, 9.","DOI":"10.3390\/biomedicines9020131"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5776\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:09:38Z","timestamp":1760162978000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5776"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,28]]},"references-count":41,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ijms22115776"],"URL":"https:\/\/doi.org\/10.3390\/ijms22115776","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2021,5,28]]}}}