Thyroid

BrixResearch_Thyroid_Brix_0

Research Projects Brix – Thyroid

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Priority Programme “THYROID TRANS ACT – Translation of Thyroid Hormone Actions beyond Classical Concepts” (SPP 1629 – Dagmar Führer, Klaudia Brix, Heike Biebermann) by the Deutsche Forschungsgemeinschaft, 2012 – 2015 – 2019. The program asked “What defines healthy and diseased thyroid function?”

The main task of the thyroid gland is the production of thyroid hormones which are essential for brain development, growth, and regulation of metabolism and body temperature. Disorders of the thyroid are frequently observed. Hypothyroidism and goiter may arise as a result of iodine deficiency. In severe cases of low-iodine diets the phenotype of cretinism still occurs. We identified thyroglobulin, the precursor of thyroid hormones, as one of the natural substrates of lysosomal cysteine peptidases. Through the use of cathepsin-deficient mouse models, we showed that the intra- and extracellular actions of cathepsins B, K, and L maintain thyroid function. Furthermore, we demonstrated the significance of cysteine cathepsin K for proper brain development in mouse models by combining behavioral studies with biochemical and cell biological approaches in order to explain the observed learning and memory phenotypes on the molecular level. Currently, we analyze auto-regulation of the thyroid gland by non-classical pathways involving thyroid hormone transporters and trace amine-associated receptors. We found that a defect in exporting thyroxine from thyroid follicles feeds back positively on its cathepsin-mediated proteolytic liberation from the precursor thyroglobulin, thereby adding to the development of auto-thyrotoxic states in Mct8 and/or Mct10 deficiencies. The data suggest TH sensing molecules within thyrocytes that contribute to thyroid auto-regulation. Recently, we have also shown that G-protein coupled receptor Taar1 is localized at the cilia of polarized thyroid epithelial cells, and it contributes to canonical TSH receptor signaling.

Supported by DFG, SFB 284, Project B9, The Foundation BLANCEFLOR, The Royal Society of Arts and Sciences in Göteborg (KVVS), Sweden, Jacobs University, and by the SPP 1629, DFG, BR1308/11-1, 11-2, 13-1, and 13-2.

References:

  • Ziros, P.G., C.O. Renaud, D.V. Chartoumpekis, M. Bongiovanni, I.G. Habeos, X.-H. Liao, S. Refetoff, P.A. Kopp, K. Brix, and G.P. Sykiotis (2020) Mice hypomorphic for Keap1, a negative regulator of the Nrf2 antioxidant response, show age-dependent diffuse goiter with elevated thyrotropin levels. Thyroid. DOI: 10.1089/thy.2020.0044
  • Biebermann, H. / K. Brix / D. Führer (2020) Seven Years of Active Thyroid Hormone Research in Germany: Thyroid Hormone Action beyond Classical Concepts. Exp. Clin. Endocrinol. Diabetes 128(6-07), 355-357. doi: 10.1055/a-1163-7355.
  • Brix, K., J. Szumska, J. Weber, M. Qatato, V. Venugopalan, A. Al-Hashimi, and M. Rehders (2020) Auto-regulation of the thyroid gland beyond classical pathways. Exp. Clin. Endocrinol. Diabetes 128(6-07), 437-445. doi: 10.1055/a-1080-2969.
  • Dauth, S., H. Rakov, R.F. Sirbulescu, I. Ilies, J. Weber, B. Batbajar Dugershaw, D. Braun, M. Rehders, E.K. Wirth, D. Führer, U. Schweizer, and K. Brix (2020) Function of cathepsin K in the central nervous system of male mice is independent of its role in the thyroid gland. Cell. Mol. Neurobiol. 40, 695-710. https://doi.org/10.1007/s10571-019-00765-6. SharedIt https://rdcu.be/b4wpt
  • Szumska, J., Z. Batool, A. Al-Hashimi / V. Venugopalan / V. Skripnik, N. Schaschke, M. Bogyo, and K. Brix (2019) Treatment of rat thyrocytes in vitro with cathepsin B and L inhibitors results in disruption of primary cilia leading to redistribution of the trace amine associated receptor 1 to the endoplasmic reticulum. Biochimie 166, 270-285. https://doi.org/10.1016/j.biochi.2019.07.010.
  • Brix, K., M. Qatato, J. Szumska, V. Venugopalan, M. Rehders (2019). Thyroglobulin storage, processing and degradation for thyroid hormone liberation. In: The Thyroid and Its Diseases, edited by Markus Luster, Leonidas Duntas, and Leonard Wartofsky. Springer International Publishing AG, part of Springer Nature 2019. https://doi.org/10.1007/978-3-319-72102-6_3
  • Brix, K. / H. Biebermann / D. Führer (2019) Priority program „Thyroid Trans Act“ (SPP1629) of the German Research Foundation – New Aspects in Thyroid Research. Nuklearmediziner 42, 1-5
  • Engels, K. / H. Rakov, G.S. Hönes, K. Brix, J. Köhrle, D. Zwanziger, L.C. Moeller, and D. Führer (2019) Aging alters phenotypic traits of thyroid dysfunction in male mice with divergent effects on complex systems but preserved thyroid hormone action in target organs. J. Gerontol. A Biol. Sci. Med. Sci. pii: glz040. doi: 10.1093/gerona/glz040
  • Qatato, M. / J. Szumska, V. Skripnik, E. Rijntjes, J. Köhrle, and K. Brix (2018). Canonical TSH Regulation of Cathepsin-Mediated Thyroglobulin Processing in the Thyroid Gland of Male Mice Requires Taar1 Expression. Front. Pharmacol. 9:221. doi: 10.3389/fphar.2018.00221.
  • Fischer, J., G. Kleinau, C. Rutz, D. Zwanziger, N. Khajavi, A. Müller, M. Rehders, K. Brix, C.L. Worth, D. Führer, H. Krude, B. Wiesner, R. Schülein / H. Biebermann (2017). Evidence of G-protein coupled receptor and substrate transporter heteromerization at a single molecule level. Cell. Mol. Life Sci.; doi.org/10.1007/s00018-017-2728-1
  • Rakov, H., K. Engels, G.S. Hönes, K. Brix, J. Köhrle, L.C. Moeller, D. Zwanziger, D. Führer (2017). Sex-specific phenotypes of hyperthyroidism and hypothyroidism in aged mice. Biology of Sex Differences 8, 38. DOI 10.1186/s13293-017-0159-1.
  • Badziong, J., S. Ting, S. Synoracki, V. Tiedje, K. Brix, G. Brabant, L.C. Moeller, K.W. Schmid, D. Führer, D. Zwanziger (2017). Differential regulation of monocarboxylate transporter 8 expression in thyroid cancer and hyperthyroidism. Eur. J. Endocrinol. 177, 243-250. Doi:10.1530/EJE-17-0279
  • Weber, J., J. McInnes, C. Kizilirmak, M. Rehders, M. Qatato, E.K. Wirth, U. Schweizer, F. Verrey, H. Heuer, and K. Brix (2017). Interdependence of thyroglobulin processing and thyroid hormone export in the mouse thyroid gland. Eur. J. Cell Biol., in press. doi: 10.1016/j.ejcb.2017.02.002
  • Engels, K. / H. Rakov, D. Zwanziger, S.G. Hoenes, M. Rehders, K. Brix, J. Köhrle, L.C. Moeller, D. Führer (2016). Efficacy of protocols for induction of chronic hyperthyroidism in male and female mice. Endocrine 54, 47-54. doi: 10.1007/s12020-016-1020-8
  • Szumska, J., M. Qatato, M. Rehders, D. Führer, H. Biebermann, D.K. Grandy, J. Köhrle, and K. Brix (2015). Trace amine-associated receptor 1 localization at the apical plasma membrane domain of Fisher rat thyroid epithelial cells is confined to cilia. Eur. Thyroid J. 4 (Suppl. 1), 30-41. doi: 10.1159/000434717
  • Führer, D. / K. Brix / H. Biebermann (2015). Understanding the healthy thyroid state in 2015. Eur. Thyroid J. 4 (Suppl. 1), 1-8. doi: 10.1159/000431318
  • Brix, K., J. McInnes, A. Al-Hashimi, M. Rehders, T. Tamhane, M.H. Haugen (2015). Proteolysis mediated by cysteine cathepsins and legumain – recent advances and cell biological challenges. Protoplasma 252, 755-774. doi: 10.1007/s00709-014-0730-0.
  • Engels, K. / H. Rakov, D. Zwanziger, L.C. Moeller, G. Homuth, J. Köhrle, K. Brix, and D. Führer (2015) Differences in mouse hepatic thyroid hormone transporter expression with age and hyperthyroidism. Eur. Thyroid J. 4 (Suppl. 1),81-86. doi: 10.1159/000381020
  • Fischer, J., G. Kleinau, A. Müller, P. Kühnen, D. Zwanziger, A. Kinne, M. Rehders, L.C. Moeller, D. Führer, A. Grüters, H. Krude, K. Brix, and H. Biebermann (2015). Modulation of monocarboxylate transporter 8 oligomerization by specific pathogenic mutations. J. Mol. Endocrinol. 54, 39-50. doi: 10.1530/JME-14-0272
  • Mühlhaus, J., J. Dinter, D. Nürnberg, M. Rehders, M. Depke, J. Golchert, G. Homuth, C.-X. Yi, S. Morin, J. Köhrle, K. Brix, M. Tschöp, G. Kleinau, and H. Biebermann (2014). Analysis of Human TAAR8 and Murine Taar8b Mediated Signaling Pathways and Expression Profile. Int. J. Mol. Sci. 15, 20638-20655. doi: 10.3390/ijms151120638
  • Führer, D. / K. Brix / H. Biebermann (2014). Übersicht / Review article: Schilddrüsenhormonwirkung – jenseits klassischer Konzepte. Das Schwerpunktprogramm „THYROID TRANS ACT“ (SPP1629) der Deutschen Forschungsgemeinschaft. Thyroid hormone action beyond classical concepts. The priority programme „THYROID TRANS ACT“ (SPP1629) of the German Research Foundation. Dtsch. Med. Wochenschr. 139, 492-496. doi:10.1055/s-0034-1369822
  • Brix, K., C.J. Scott, M.M.S. Heck (2013) Compartmentalization of Proteolysis. In: Proteases: Structure and Function, edited by Klaudia Brix and Walter Stöcker, Springer-Verlag Wien. http://www.springer.com/gp/book/9783709108840#otherversion=9783709108857
  • Brix, K. / D. Führer / H. Biebermann (2011). Molecules important for thyroid hormone synthesis and action – known facts and future perspectives. Thyroid Research 4 (Suppl 1), S9. doi:10.1186/1756-6614-4-S1-S9
  • Tedelind, S., S. Jordans, H. Resemann, G. Blum, M. Bogyo, D. Führer, and K. Brix (2011). Cathepsin B trafficking in thyroid carcinoma cells. Thyroid Research 4 (Suppl 1), S2. doi:10.1186/1756-6614-4-S1-S2
  • Dauth, S., M. Arampatzidou, M. Rehders, D.M.T. Yu, D. Führer, and K. Brix (2011). Thyroid cathepsin K – roles in physiology and thyroid disease. Clin. Rev. Bone Miner. Metab. 9, 94-106. doi:10.1007/s12018-011-9093-7
  • Arampatzidou, M., M. Rehders, S. Dauth, D.M.T. Yu, S. Tedelind, and K. Brix (2011). Imaging of protease functions – current guide to spotting cysteine cathepsins in classical and novel scenes of action in mammalian epithelial cells and tissues. It. J. Anat. Embryol. 116, 1-19.
  • Tedelind, S., K. Poliakova, A. Valeta, R. Hunegnaw, E. Lemma Yemanaberhan, N.-E. Heldin, J. Kurebayashi, E. Weber, N. Kopitar-Jerala, B. Turk, M. Bogyo, and K. Brix (2010). Nuclear cysteine cathepsin variants in thyroid carcinoma cells. Biol. Chem. 391, 923-935.
  • Jordans, S., S. Jenko-Kokalj, N.M. Kühl, S. Tedelind, W. Sendt, D. Brömme, D. Turk, and K. Brix (2009). Monitoring compartment-specific substrate cleavage by cathepsins B, K, L, and S at physiological pH and redox conditions. BMC Biochemistry 10, 23. doi:10.1186/1471-2091-10-23
  • Brix, K., A. Dunkhorst, K. Mayer, and S. Jordans (2008). Cysteine cathepsins: Cellular roadmap to different functions. Biochimie 90, 194-207. doi:10.1016/j.biochi.2007.07.024
  • Brix, K., and S. Jordans (2005). News & Views: Watching proteases in action. Nature Chem. Biol. 1, 186-187.
  • Brix, K. (2005). Chapter 05: Lysosomal Proteases: Revival of the Sleeping Beauty. In: Lysosomes, edited by Paul Saftig, Eurekah.com. Landes Bioscience. http://www.eurekah.com/abstract.php?chapid=2255&bookid=129&catid=15
  • Friedrichs, B., C. Tepel, Th. Reinheckel, J. Deussing, K. von Figura, V. Herzog, Ch. Peters, P. Saftig, and K. Brix (2003). Thyroid functions of mouse cathepsins B, K, and L. J. Clin. Invest. 111, 1733-1745.
  • Linke, M., V. Herzog, and K. Brix (2002). Trafficking of lysosomal cathepsin B – green fluorescent protein to the surface of thyroid epithelial cells involves the endosomal/lysosomal compartment. J. Cell Sci. 115, 4877-4889.
  • Linke, M., S. Jordans, L. Mach, V. Herzog, and K. Brix (2002). Thyroid stimulating hormone upregulates secretion of cathepsin B from thyroid epithelial cells. Biol. Chem. 383, 773-784.
  • Brix, K., M. Linke, C. Tepel, and V. Herzog (2001). Cysteine proteinases mediate extracellular prohormone processing in the thyroid. Biol. Chem. 382, 717-725.
  • Hitzel, C., H. Kanzler, A. König, M.P. Kummer, K. Brix, V. Herzog, and N. Koch (2000). Thyroglobulin type I-like domains in invariant chain fusion proteins mediate resistance to cathepsin L digestion. FEBS Lett. 485, 67-70.
  • Tepel, C., D. Brömme, V. Herzog, and K. Brix (2000). Cathepsin K in thyroid epithelial cells: Sequence, localization, and possible function in extracellular proteolysis of thyroglobulin. J. Cell Sci. 113, 4487-4498.
  • Saber-Lichtenberg, Y., K. Brix, A. Schmitz, J.E. Heuser, J.H. Wilson, L. Lorand, and V. Herzog (2000). Covalent cross-linking of secreted bovine thyroglobulin by transglutaminase. FASEB J. 14, 1005-1014.
  • Dombrowski, F., L. Klotz, H.J. Hacker, Y. Li, D. Klingmüller, K. Brix, V. Herzog, and P. Bannasch (2000). Hyperproliferative hepatocellular alterations after intraportal transplantation of thyroid follicles. Am. J. Pathol. 156, 99-113.
  • Lemansky, P., K. Brix, and V. Herzog (1999). Subcellular distribution, secretion and posttranslational modifications of clusterin in thyrocytes. Exp. Cell Res. 251, 147-155.
  • Brix, K., W. Summa, F. Lottspeich, and V. Herzog (1998). Extracellularly occuring histone H1 mediates the binding of thyroglobulin to the cell surface of mouse macrophages. J. Clin. Invest. 102, 283-293.
  • Lemansky, P., K. Brix, and V. Herzog (1998). Iodination of mature cathepsin D in thyrocytes as an indicator for its transport to the cell surface. Eur. J. Cell Biol. 76, 53-62.
  • Brix, K., R. Wirtz, and V. Herzog (1997). Paracrine interaction between hepatocytes and macrophages after extrathyroidal proteolysis of thyroglobulin. Hepatology 26, 1232-1240.
  • Graebert, K.S., H. Bauch, W. Neumüller, K. Brix, and V. Herzog (1997). Epithelial folding in vitro: Studies on the cellular mechanism underlying evagination of thyrocyte monolayers. Exp. Cell Res. 231, 214-225.
  • Brix, K., P. Lemansky, and V. Herzog (1996). Evidence for extracellularly acting cathepsins mediating thyroid hormone liberation in thyroid epithelial cells. Endocrinology 137, 1963-1974.
  • Brix, K., and V. Herzog (1994). Extrathyroidal release of thyroid hormones from thyroglobulin by J774 mouse macrophages. J. Clin. Invest. 93, 1388-1396.