The successful iodination of thyroglobulin (Tg) leading to coupling of di-iodotyrosyl residues within Tg for the synthesis of thyroxine (the major form of thyroid hormone produced by the thyroid gland), requires that the thyrocyte precisely coordinate a number of distinct cell surface activities. Amongst other proteins, on the basolateral cell surface resides the thyrotropin (TSH) receptor, sodium/potassium ATPase, and sodium-iodide symporter (NIS), while the apical cell surface expresses thyroperoxidase (TPO) and pendrin activities, not to mention the production and release of hydrogen peroxide and the exocytosis of newly-synthesized Tg for hormonogenesis via a """"""""last-come, first-served"""""""" mechanism. This grant, which serves as the sole source of thyroid-related funding for our lab, covers a spectrum of related topics pertinent to thyrocyte cell biology, with a focus on secretory pathway delivery of proteins essential for thyroid function. In earlier cycles of this grant, we defined steps in the normal folding pathway of newly-synthesized Tg; determined that the human illness described as """"""""congenital goiter with deficient thyroglobulin"""""""" is an endoplasmic reticulum storage disease caused by the misfolding and ER retention of mutant Tg (mediated by ER-specific molecular chaperones); and identified the cog/cog mouse as a putative animal model of this illness. In papers published in the most recent five years of this grant (1997-2002), among other findings, we have pinpointed the molecular defect in the cog cog mouse as a single point mutation more than 2,000 amino acids downstream in the Tg coding sequence, and we began to concentrate on the intracellular disposal of the mutant Tg protein by ER-associated degradation (ERAD). We now present compelling evidence to support that the protein domain harboring the cog mutation -- the acetylcholinesterase-(AChE)-Iike domain, plays an essential role in normal Tg folding and homodimerization. By replacing this domain with authentic AChE (which also homodimerizes), we have created a powerful new enzymatically-active native reporter at the C-terminus of Tg, greatly enabling studies of Tg intracellular transport (Aim 1). We also wish to examine quality control signaling proteins and their roles in the ER retention and ERAD of mutant Tg (Aims 2 and 3). Finally we have made steady progress in our studies of the trafficking of TPO (and there are a few surprises!), and we now propose to take these studies in new directions relating to surface expression in both thyrocyte cell lines and the thyroid gland in situ (Aim 4).

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK040344-19
Application #
6916179
Study Section
Endocrinology Study Section (END)
Program Officer
Haft, Carol R
Project Start
1988-09-01
Project End
2008-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
19
Fiscal Year
2005
Total Cost
$452,387
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Citterio, Cintia E; Morishita, Yoshiaki; Dakka, Nada et al. (2018) Relationship between the dimerization of thyroglobulin and its ability to form triiodothyronine. J Biol Chem 293:4860-4869
Citterio, Cintia E; Veluswamy, Balaji; Morgan, Sarah J et al. (2017) De novo triiodothyronine formation from thyrocytes activated by thyroid-stimulating hormone. J Biol Chem 292:15434-15444
Qi, Ling; Tsai, Billy; Arvan, Peter (2017) New Insights into the Physiological Role of Endoplasmic Reticulum-Associated Degradation. Trends Cell Biol 27:430-440
Di Jeso, Bruno; Arvan, Peter (2016) Thyroglobulin From Molecular and Cellular Biology to Clinical Endocrinology. Endocr Rev 37:2-36
Holzer, Guillaume; Morishita, Yoshiaki; Fini, Jean-Baptiste et al. (2016) Thyroglobulin Represents a Novel Molecular Architecture of Vertebrates. J Biol Chem 291:16553-66
Di Jeso, Bruno; Morishita, Yoshiaki; Treglia, Antonella S et al. (2014) Transient covalent interactions of newly synthesized thyroglobulin with oxidoreductases of the endoplasmic reticulum. J Biol Chem 289:11488-96
Wright, Jordan; Wang, Xiaofan; Haataja, Leena et al. (2013) Dominant protein interactions that influence the pathogenesis of conformational diseases. J Clin Invest 123:3124-34
Ferris, Sean P; Jaber, Nikita S; Molinari, Maurizio et al. (2013) UDP-glucose:glycoprotein glucosyltransferase (UGGT1) promotes substrate solubility in the endoplasmic reticulum. Mol Biol Cell 24:2597-608
Gualeni, Benedetta; Rajpar, M Helen; Kellogg, Aaron et al. (2013) A novel transgenic mouse model of growth plate dysplasia reveals that decreased chondrocyte proliferation due to chronic ER stress is a key factor in reduced bone growth. Dis Model Mech 6:1414-25
Lee, Jaemin; Di Jeso, Bruno; Arvan, Peter (2011) Maturation of thyroglobulin protein region I. J Biol Chem 286:33045-52

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