Lack of L-type amino acid transporter 2 in murine thyroid tissue induces autophagy

in Journal of Molecular Endocrinology
Authors:
Vaishnavi Venugopalan School of Science, Jacobs University Bremen, Bremen, Germany

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Maren Rehders School of Science, Jacobs University Bremen, Bremen, Germany

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Jonas Weber School of Science, Jacobs University Bremen, Bremen, Germany

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Lisa Rodermund School of Science, Jacobs University Bremen, Bremen, Germany

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Alaa Al-Hashimi School of Science, Jacobs University Bremen, Bremen, Germany

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Tonia Bargmann School of Science, Jacobs University Bremen, Bremen, Germany

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Janine Golchert Department of Functional Genomics, University Medicine Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Greifswald, Germany

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Vivien Reinecke Department of Functional Genomics, University Medicine Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Greifswald, Germany

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Georg Homuth Department of Functional Genomics, University Medicine Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Greifswald, Germany

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Uwe Völker Department of Functional Genomics, University Medicine Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Greifswald, Germany

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Francois Verrey Physiologisches Institut, Universität Zürich, Zürich, Switzerland

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Janine Kirstein Fachbereich 2 Biologie/Chemie, Faculty of Cell Biology, Universität Bremen, Bremen, Germany

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Heike Heuer Department of Endocrinology, Diabetes and Metabolism, Universitätsklinikum Essen, Essen, Germany

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Ulrich Schweizer Institut für Biochemie und Molekularbiologie, Medizinische Fakultät, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany

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Doreen Braun Institut für Biochemie und Molekularbiologie, Medizinische Fakultät, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany

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Eva K Wirth Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
Department of Endocrinology and Metabolism, Berlin Institute of Health, Berlin, Germany
DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany

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Klaudia Brix School of Science, Jacobs University Bremen, Bremen, Germany

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Correspondence should be addressed to K Brix: k.brix@jacobs-university.de
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Proteolytic cleavage of thyroglobulin (Tg) for thyroid hormone (TH) liberation is followed by TH release from thyroid follicles into the circulation, enabled by TH transporters. The existence of a functional link between Tg-processing cathepsin proteases and TH transporters has been shown to be independent of the hypothalamus–pituitary–thyroid axis. Thus, lack of cathepsin K, combined with genetic defects in the TH transporters Mct8 and Mct10, that is the Ctsk −/−/Mct8 −/y/Mct10 −/− genotype, results in persistent Tg proteolysis due to autophagy induction. Because amino acid transport by L-type amino acid transporter 2 (Lat2) has been described to regulate autophagy, we asked whether Lat2 availability is affected in Ctsk −/−/Mct8 −/y/Mct10 −/− thyroid glands. Our data revealed that while mRNA amounts and subcellular localization of Lat2 remained unaltered in thyroid tissue of Ctsk −/−/Mct8 −/y/Mct10 −/− mice in comparison to WT controls, the Lat2 protein amounts were significantly reduced. These data suggest a direct link between Lat2 function and autophagy induction in Ctsk −/−/Mct8 −/y/Mct10 −/− mice. Indeed, thyroid tissue of Lat2 −/− mice showed enhanced endo-lysosomal cathepsin activities, increased autophagosome formation, and enhanced autophagic flux. Collectively, these results suggest a mechanistic link between insufficient Lat2 protein function and autophagy induction in the thyroid gland of male mice.

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