De Novo Triiodothyronine Formation from Thyrocytes Activated by Thyroid-Stimulating Hormone

Authors

Cintia E. Citterio, Chapman UniversityFollow
Balaji Veluswamy, University of Michigan, Ann Arbor
Sarah J. Morgan, National Institutes of Health
Valerie A. Galton, Dartmouth College
J. Paul Banga, University of Duisburg-Essen
Stephen Atkins, University of Michigan, Ann Arbor
Yoshiaki Morishita, University of Michigan, Ann Arbor
Susanne Neumann, National Institutes of Health
Rauf Latif, The Icahn School of Medicine at Mount Sinai
Marvin C. Gershengorn, National Institutes of Health
Terry J. Smith, University of Michigan, Ann Arbor
Peter Arvan, University of Michigan, Ann Arbor

Document Type

Article

Publication Date

7-25-2017

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.

Comments

This article was originally published in Journal of Biological Chemistry, volume 292, issue 37, in 2017. https://doi.org/10.1074/jbc.M117.784447

Recommended Citation

C. E. Citterio, B. Veluswamy, S. J. Morgan, V. A. Galton, J. P. Banga, S. Atkins, Y. Morishita, S. Neumann, R. Latif, M. C. Gershengorn, T. J. Smith, and P. Arvan (2017). De novo Triiodothyronine Formation from Thyrocytes Activated by Thyroid-Stimulating Hormone. J Biol Chem. 292 (37) 15434–15444. https://doi.org/10.1074/jbc.M117.784447

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