ECE2021 Presented Eposters Presented ePosters 15: Late Breaking (8 abstracts)
Monocarboxylate transporter 8 deficiency leads to autophagy-induced persistent cathepsin-mediated thyroglobulin processing triggered by insufficient L-type amino acid transporter 2 functionality
Vaishnavi Venugopalan 1 , Alaa Al-Hashimi 1 , Jonas Weber 1 , Maren Rehders 1 , Janine Golchert 2 , Georg Homuth 2 , Francois Verrey 3 , Janine Kirstein 4 , Heike Heuer 5 , Ulrich Schweizer 6 , Eva Wirth 7 & Klaudia Brix 1
1Jacobs University Bremen, Department of Life Sciences and Chemistry, Focus Area HEALTH, Bremen, Germany; 2University Medicine Greifswald, Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, Greifswald, Germany; 3University of Zurich, Institute of Physiology, Zurich, Switzerland; 4University of Bremen, Faculty of Cell Biology, Bremen, Germany; 5Universitätsklinikum Essen, Department of Endocrinology, Diabetes and Metabolism, Essen, Germany; 6Universität Bonn, Institut für Biochemie und Molekularbiologie, Medizinische Fakultät, Bonn, Germany; 7 Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Department of Endocrinology and Metabolism and DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany
The thyroid gland functions in supplying thyroid hormones (TH) to the body periphery, which is enabled by cathepsin-mediated thyroglobulin proteolysis and TH translocation across membranes by the Mct8, Mct10, and Lat2 transporters. Previously, we showed that cathepsin K-deficient mice feature normal thyroid phenotypes which is, in part, due to the functional compensation through cathepsin L upregulation that is independent of the classical hypothalamus–pituitary–thyroid axis. These results imply that intrathyroidal TH-sensing mechanisms exist. Since cathepsin K deficiency correlated with increased Mct8 protein amounts, we aimed to understand if TH transporters are part of such thyroid auto-regulatory mechanisms. Therefore, in a murine model, 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-/-. Our results show that, albeit impaired TH export, Ctsk-/-/Mct8/y/Mct10/ mice feature thyrotoxic stress-triggered autophagy induction, which results in persistent thyroglobulin proteolysis due to enhanced lysosomal biogenesis. Furthermore, we aimed to elucidate what triggers autophagy in Ctsk-/-/Mct8-/y/Mct10-/- thyroid glands. Lat2 has been implicated as a sensor of amino acids in kidney and muscle, where it is believed to activate mTORC1, a negative regulator of autophagy. Since TH as iodothyronines are amino acid derivatives, we propose that Lat2 might be involved in sensing of intrathyroidal cytosolic TH states in Ctsk/-/Mct8/y/Mct10-/- mice, thereby inducing autophagy when TH export is lacking. Although no significant changes were observed in Lat2 mRNA levels in the triple-deficient thyroids in comparison to wild-type controls, Lat2 immunoblotting showed significantly reduced protein amounts. In addition, immunofluorescence staining demonstrated decreased Lat2-specific signals, while Lat2 sub-cellular localization in thyrocytes of Ctsk-/-/Mct8/y/Mct10-/- mice remained unaltered, suggesting a direct link between diminished Lat2 and autophagy induction in Ctsk-/-/Mct8/y/Mct10-/- mice. To support this hypothesis, we investigated autophagy-mediated lysosomal biogenesis in Lat2 deficiency. Indeed, Lat2 deficiency was accompanied by enhanced cathepsin levels and activity, increased autophagosome formation, and enhanced autophagic flux. Collectively, we conclude that insufficient Lat2 functionality in triple-deficient mice leads to a reduction in intrathyroidal TH sensing capabilities, thereby failing to activate mTORC1, and consequently triggering autophagy. In addition, autophagy induction results in the biosynthesis of lysosomal proteins which could explain the enhanced cathepsin-mediated thyroglobulin degradation and Lat2 protein instability in Ctsk//Mct8/y/Mct10/- mice.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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