De novo triiodothyronine formation from thyrocytes activated by Thyroid Stimulating Hormone

TERRY J. SMITH; SUSANNE NEUMANN; J. PAUL BANGA; BALAJI VELUSWAMY; PETER ARVAN; RAUF LATIF; STEPHEN ATKINS; SARAH J. MORGAN; MARVIN C. GERSHENGORN; YOSHIAKI MORISHITA; VALERIE A. GALTON; CINTIA E. CITTERIO

JOURNAL OF BIOLOGICAL CHEMISTRY (ONLINE)

The American Society for Biochemistry and Molecular Biology (ASBMB)

Año: 2017 vol. 292 p. 15434 - 15444

1083-351X

The thyroid gland secretes primarilytetraiodothyronine (T4), and sometriiodothyronine (T3). Under normalphysiological circumstances, only one-fifth ofcirculating T3 is directly released by the thyroid,but in states of hyperactivation of thyroidstimulating-hormone receptors (TSHRs), patientsdevelop a syndrome of relative T3-toxicosis.Thyroidal T4 production results from iodinationof thyroglobulin (TG) at residues Tyr5 andTyr130, whereas thyroidal T3 production mayoriginate in several different ways. In this study,the data demonstrate that within the carboxylterminalportion of mouse TG, T3 is formed denovo independently of deiodination from T4. Wefound that upon iodination in vitro, de novo T3formation in TG was decreased in mice lackingTSHRs. Conversely, de novo T3 that can beformed upon iodination of TG secreted fromPCCL3 (rat thyrocyte) cells was augmented fromcells previously exposed to increased TSH, aTSHR agonist, a cAMP analog, or a TSHRstimulatingantibody. We present data suggestingthat TSH-stimulated TG phosphorylationcontributes to enhanced de novo T3 formation.These effects were reversed within a few daysafter removal of the hyperstimulating conditions.Indeed, direct exposure of PCCL3 cells to humanserum from two patients with Graves? disease,but not control sera, led to secretion of TG withan increased intrinsic ability to form T3 upon invitro iodination. Further, TG secreted fromhuman thyrocyte cultures hyperstimulated withTSH also showed an increased intrinsic ability toform T3. Our data support the hypothesis that TGprocessing in the secretory pathway of TSHRhyperstimulatedthyrocytes alters the structure ofthe iodination substrate in a way that enhancesde novo T3 formation, contributing to the relativeT3-toxicosis of Graves? disease.