{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:51:31Z","timestamp":1760161891048,"version":"build-2065373602"},"reference-count":86,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,1,5]],"date-time":"2021-01-05T00:00:00Z","timestamp":1609804800000},"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 and 11-2","SCHW 914\/6-1","HE 3418\/7-1 and 7-2","HO 2140\/6-2","KI 1988\/5-1"],"award-info":[{"award-number":["BR 1308\/11-1 and 11-2","SCHW 914\/6-1","HE 3418\/7-1 and 7-2","HO 2140\/6-2","KI 1988\/5-1"]}],"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"}]},{"name":"Schweizerischer Nationalfonds zur F&amp;#x00F6;rderung der Wissenschaftlichen Forschung","award":["#31_166430\/1"],"award-info":[{"award-number":["#31_166430\/1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The thyroid gland is both a thyroid hormone (TH) generating as well as a TH responsive organ. It is hence crucial that cathepsin-mediated proteolytic cleavage of the precursor thyroglobulin is regulated and integrated with the subsequent export of TH into the blood circulation, which is enabled by TH transporters such as monocarboxylate transporters Mct8 and Mct10. Previously, we showed that cathepsin K-deficient mice exhibit the phenomenon of functional compensation through cathepsin L upregulation, which is independent of the canonical hypothalamus-pituitary-thyroid axis, thus, due to auto-regulation. Since these animals also feature enhanced Mct8 expression, we aimed to understand if TH transporters are part of the thyroid auto-regulatory mechanisms. Therefore, we analyzed phenotypic differences in thyroid function arising from combined cathepsin K and TH transporter deficiencies, i.e., in Ctsk-\/-\/Mct10-\/-, Ctsk-\/-\/Mct8-\/y, and Ctsk-\/-\/Mct8-\/y\/Mct10-\/-. Despite the impaired TH export, thyroglobulin degradation was enhanced in the mice lacking Mct8, particularly in the triple-deficient genotype, due to increased cathepsin amounts and enhanced cysteine peptidase activities, leading to ongoing thyroglobulin proteolysis for TH liberation, eventually causing self-thyrotoxic thyroid states. The increased cathepsin amounts were a consequence of autophagy-mediated lysosomal biogenesis that is possibly triggered due to the stress accompanying intrathyroidal TH accumulation, in particular in the Ctsk-\/-\/Mct8-\/y\/Mct10-\/- animals. Collectively, our data points to the notion that the absence of cathepsin K and Mct8 leads to excessive thyroglobulin degradation and TH liberation in a non-classical pathway of thyroid auto-regulation.<\/jats:p>","DOI":"10.3390\/ijms22010462","type":"journal-article","created":{"date-parts":[[2021,1,5]],"date-time":"2021-01-05T21:18:57Z","timestamp":1609881537000},"page":"462","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Thyroid Hormone Transporter Mct8 Restricts Cathepsin-Mediated Thyroglobulin Processing in Male Mice through Thyroid Auto-Regulatory Mechanisms That Encompass Autophagy"],"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-29759 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-29759 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-29759 Bremen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janine","family":"Golchert","sequence":"additional","affiliation":[{"name":"Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Felix-Hausdorff-Str. 8, 17475 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivien","family":"Reinecke","sequence":"additional","affiliation":[{"name":"Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Felix-Hausdorff-Str. 8, 17475 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6839-0605","authenticated-orcid":false,"given":"Georg","family":"Homuth","sequence":"additional","affiliation":[{"name":"Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Felix-Hausdorff-Str. 8, 17475 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5689-3448","authenticated-orcid":false,"given":"Uwe","family":"V\u00f6lker","sequence":"additional","affiliation":[{"name":"Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Felix-Hausdorff-Str. 8, 17475 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mythili","family":"Manirajah","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Chemistry, Focus Area HEALTH, Jacobs University Bremen, Campus Ring 1, D-29759 Bremen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7398-2314","authenticated-orcid":false,"given":"Adam","family":"Touzani","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Chemistry, Focus Area HEALTH, Jacobs University Bremen, Campus Ring 1, D-29759 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-29759 Bremen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew S.","family":"Bogyo","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Stanford University, 300 Pasteur Dr., Stanford, CA 94305-5324, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francois","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\/0000-0002-0491-9941","authenticated-orcid":false,"given":"Eva K.","family":"Wirth","sequence":"additional","affiliation":[{"name":"Berlin Institute of Health, Department of Endocrinology and Metabolism, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, Hessische Str. 3-4, Germany and DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, D-10115 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrich","family":"Schweizer","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Biochemie und Molekularbiologie, Medizinische Fakult\u00e4t, Universit\u00e4t Bonn, Nu\u00dfallee 11, D-53115 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heike","family":"Heuer","sequence":"additional","affiliation":[{"name":"Klinik f\u00fcr Endokrinologie, Diabetologie und Stoffwechsel, Universit\u00e4tsklinikum Essen (A\u00f6R), Universit\u00e4t Duisburg-Essen, Hufelandstr. 55, D-45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4990-2497","authenticated-orcid":false,"given":"Janine","family":"Kirstein","sequence":"additional","affiliation":[{"name":"Fachbereich 2 Biologie\/Chemie, Faculty of Cell Biology, Universit\u00e4t Bremen, Leobener Stra\u00dfe 5, D-28359 Bremen, Germany"}],"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-29759 Bremen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/S0074-7696(08)60848-7","article-title":"Functional Morphology of the Thyroid","volume":"Volume 113","author":"Jeon","year":"1988","journal-title":"International Review of Cytology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/B978-0-12-416021-7.00004-3","article-title":"Mechanisms of thyroid development and dysgenesis: An analysis based on developmental stages and concurrent 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