De novo triiodothyronine formation from thyrocytes activated by Thyroid-stimulating hormone
| Autor: | Sarah J. Morgan, Yoshiaki Morishita, Stephen J. Atkins, Balaji Veluswamy, Peter Arvan, Marvin C. Gershengorn, Valerie Anne Galton, J. Paul Banga, Rauf Latif, Cintia Eliana Citterio, Terry J. Smith, Susanne Neumann |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
endocrine system medicine.medical_specialty CIENCIAS MÉDICAS Y DE LA SALUD endocrine system diseases Graves' disease medicine.medical_treatment Medizin Inmunología Protein processing Biochemistry Thyroglobulin 03 medical and health sciences Thyroid-stimulating hormone Internal medicine medicine Secretion Molecular Biology Thyroid Epithelial Cells Triiodothyronine Chemistry Iodination Thyroid Molecular Bases of Disease Cell Biology purl.org/becyt/ford/3.1 [https] medicine.disease Thyroid hormone Medicina Básica 030104 developmental biology Endocrinology medicine.anatomical_structure Hormone receptor purl.org/becyt/ford/3 [https] Protein secretion |
| Zdroj: | CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET |
| DOI: | 10.1074/jbc.M117.784447 |
| Popis: | The thyroid gland secretes primarily tetraiodothyronine (T4), and some triiodothyronine (T3). Under normal physiological circumstances, only one-fifth of circulating T3 is directly released by the thyroid, but in states of hyperactivation of thyroid-stimulating hormone receptors (TSHRs), patients develop a syndrome of relative T3 toxicosis. Thyroidal T4 production results from iodination of thyroglobulin (TG) at residues Tyr5 and Tyr130, whereas thyroidal T3 production may originate in several different ways. In this study, the data demonstrate that within the carboxyl-terminal portion of mouse TG, T3 is formed de novo independently of deiodination from T4. We found that upon iodination in vitro, de novo T3 formation in TG was decreased in mice lacking TSHRs. Conversely, de novo T3 that can be formed upon iodination of TG secreted from PCCL3 (rat thyrocyte) cells was augmented from cells previously exposed to increased TSH, a TSHR agonist, a cAMP analog, or a TSHR-stimulating antibody. We present data suggesting that TSH-stimulated TG phosphorylation contributes to enhanced de novo T3 formation. These effects were reversed within a few days after removal of the hyperstimulating conditions. Indeed, direct exposure of PCCL3 cells to human serum from two patients with Graves’ disease, but not control sera, led to secretion of TG with an increased intrinsic ability to form T3 upon in vitro iodination. Furthermore, TG secreted from human thyrocyte cultures hyperstimulated with TSH also showed an increased intrinsic ability to form T3. Our data support the hypothesis that TG processing in the secretory pathway of TSHR-hyperstimulated thyrocytes alters the structure of the iodination substrate in a way that enhances de novo T3 formation, contributing to the relative T3 toxicosis of Graves’ disease. Fil: Citterio, Cintia Eliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina. University of Michigan; Estados Unidos Fil: Veluswamy, Balaji. University of Michigan; Estados Unidos Fil: Morgan, Sarah J.. National Institutes of Health; Estados Unidos Fil: Galton, Valerie A.. Geisel School of Medicine at Dartmouth; Estados Unidos Fil: Banga, J. Paul. Universitat Essen; Alemania Fil: Atkins, Stephen. University of Michigan; Estados Unidos Fil: Morishita, Yoshiaki. University of Michigan; Estados Unidos Fil: Neumann, Susanne. National Institutes of Health; Estados Unidos Fil: Latif, Rauf. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Gershengorn, Marvin. National Institutes of Health; Estados Unidos Fil: Smith, Terry J.. University of Michigan; Estados Unidos Fil: Arvan, Peter. University of Michigan; Estados Unidos |
| Databáze: | OpenAIRE |
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