Thyroid

BrixResearch_Thyroid_Brix_0

Research Projects Brix – Thyroid

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 – 2018. The program asks “What defines healthy and diseased thyroid function?” See: www.thyroidtransact.de

SPP1629_logo_2012-200x150-100x75

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.

Collaboration with Christoph Peters & Thomas Reinheckel, Freiburg, Paul Saftig, Kiel, Nisse Heldin, Uppsala, Junichi Kurebayashi, Okayama, Boris Turk, Ljubljana, Dieter Brömme, Vancouver, Dusan Turk, Ljubljana, Heike Biebermann, Berlin, Dagmar Führer, Essen, Heike Heuer, Düsseldorf/Jena, Ulrich Schweizer, Bonn, Eva K. Wirth, Berlin, Josef Köhrle, Berlin, Lars Moeller, Essen, Georg Homuth, Henri Wallaschofski, Uwe Völker, Greifswald; 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:

BOOK CHAPTERS:

Brix, K., M. Qatato, J. Szumska, V. Venugopalan, M. Rehders (in press). Thyroglobulin storage and degradation for thyroid hormone liberation. In: The Thyroid and Its Diseases, edited by Markus Luster, Leonidas Duntas, and Leonard Wartofsky. Springer-Verlag, Heidelberg.

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. (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

 

  • 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., in press. 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. / 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.
  • 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.