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J Biol Chem. 2017 Sep 15;292(37):15434-15444. doi: 10.1074/jbc.M117.784447. Epub 2017 Jul 25.

De novo triiodothyronine formation from thyrocytes activated by thyroid-stimulating hormone.

Author information

1
From the Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan 48105.
2
the Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología y Biotecnología/Cátedra de Genética, C1113AAD Buenos Aires, Argentina.
3
the CONICET-Universidad de Buenos Aires, Instituto de Inmunología, Genética y Metabolismo (INIGEM), C1120AAR Buenos Aires, Argentina.
4
the National Institutes of Health, NIDDK, Laboratory of Endocrinology and Receptor Biology (LERB), Bethesda, Maryland 20892.
5
the Department of Physiology and Neurobiology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756.
6
the Department of Molecular Ophthalmology, University of Duisburg-Essen, 45147 Essen, Germany.
7
the Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan 48105, and.
8
the Thyroid Research Unit, James J. Peters Veterans Affairs Medical Center, The Icahn School of Medicine at Mount Sinai, New York, New York 10468.
9
From the Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan 48105, parvan@umich.edu.

Abstract

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.

KEYWORDS:

Graves' Disease; iodination; post-translational modification (PTM); protein processing; protein secretion; thyroglobulin; thyroid; thyroid hormone

PMID:
28743746
PMCID:
PMC5602401
DOI:
10.1074/jbc.M117.784447
[Indexed for MEDLINE]
Free PMC Article

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