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The Thyroid Hormone Transporter Mct8 Restricts Cathepsin-Mediated Thyroglobulin Processing in Male Mice through Thyroid Auto-Regulatory Mechanisms That Encompass Autophagy

1
Department of Life Sciences and Chemistry, Focus Area HEALTH, Jacobs University Bremen, Campus Ring 1, D-29759 Bremen, Germany
2
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Felix-Hausdorff-Str. 8, 17475 Greifswald, Germany
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Department of Pathology, School of Medicine, Stanford University, 300 Pasteur Dr., Stanford, CA 94305-5324, USA
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Physiologisches Institut, Universität Zürich, Winterthurerstr. 190, CH-8057 Zürich, Switzerland
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Berlin Institute of Health, Department of Endocrinology and Metabolism, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Hessische Str. 3-4, Germany and DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, D-10115 Berlin, Germany
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Institut für Biochemie und Molekularbiologie, Medizinische Fakultät, Universität Bonn, Nußallee 11, D-53115 Bonn, Germany
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Klinik für Endokrinologie, Diabetologie und Stoffwechsel, Universitätsklinikum Essen (AöR), Universität Duisburg-Essen, Hufelandstr. 55, D-45147 Essen, Germany
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Fachbereich 2 Biologie/Chemie, Faculty of Cell Biology, Universität Bremen, Leobener Straße 5, D-28359 Bremen, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(1), 462; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010462
Received: 30 October 2020 / Revised: 17 December 2020 / Accepted: 29 December 2020 / Published: 5 January 2021
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. View Full-Text
Keywords: autophagy; cathepsins; lysosomal biogenesis; monocarboxylate transporter 8; thyroid auto-regulation autophagy; cathepsins; lysosomal biogenesis; monocarboxylate transporter 8; thyroid auto-regulation
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MDPI and ACS Style

Venugopalan, V.; Al-Hashimi, A.; Rehders, M.; Golchert, J.; Reinecke, V.; Homuth, G.; Völker, U.; Manirajah, M.; Touzani, A.; Weber, J.; Bogyo, M.S.; Verrey, F.; Wirth, E.K.; Schweizer, U.; Heuer, H.; Kirstein, J.; Brix, K. 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. 2021, 22, 462. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010462

AMA Style

Venugopalan V, Al-Hashimi A, Rehders M, Golchert J, Reinecke V, Homuth G, Völker U, Manirajah M, Touzani A, Weber J, Bogyo MS, Verrey F, Wirth EK, Schweizer U, Heuer H, Kirstein J, Brix K. The Thyroid Hormone Transporter Mct8 Restricts Cathepsin-Mediated Thyroglobulin Processing in Male Mice through Thyroid Auto-Regulatory Mechanisms That Encompass Autophagy. International Journal of Molecular Sciences. 2021; 22(1):462. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010462

Chicago/Turabian Style

Venugopalan, Vaishnavi, Alaa Al-Hashimi, Maren Rehders, Janine Golchert, Vivien Reinecke, Georg Homuth, Uwe Völker, Mythili Manirajah, Adam Touzani, Jonas Weber, Matthew S. Bogyo, Francois Verrey, Eva K. Wirth, Ulrich Schweizer, Heike Heuer, Janine Kirstein, and Klaudia Brix. 2021. "The Thyroid Hormone Transporter Mct8 Restricts Cathepsin-Mediated Thyroglobulin Processing in Male Mice through Thyroid Auto-Regulatory Mechanisms That Encompass Autophagy" International Journal of Molecular Sciences 22, no. 1: 462. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010462

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