Journal of Biological Chemistry
Volume 270, Issue 50, 15 December 1995, Pages 29881-29888
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Carbohydrates, Lipids, and Other Natural Products
N-Glycans Modulate in Vivo and in Vitro Thyroid Hormone Synthesis: STUDY AT THE N-TERMINAL DOMAIN OF THYROGLOBULIN (∗)

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Thyroglobulin (Tg) is the substrate for thyroid hormone biosynthesis, which requires tyrosine iodination and iodotyrosine coupling and occurs at the apical membrane of the thyrocytes. Tg glycoconjugates have been shown to play a major role in Tg routing through cellular compartments and recycling after endocytosis. Here we show that glycoconjugates also play a direct role in hormonosynthesis. The N-terminal domain (NTD; Asn1-Met171) of human Tg, which bears the preferential hormonogenic site, brings two N-glycans (Asn57 and Asn91). NTD preparations were purified from Tg with low and mild iodine content in vivo and from poorly iodinated Tg after in vitro iodination and coupling. NTD separated from poorly iodinated Tg was also submitted to iodination and coupling after desialylation and deglycosylation. The various NTD isoforms were analyzed for their N-glycan structures and hormone contents. Our results show that 1) in vivo as well as in vitro unglycosylated isoforms did not synthesize hormones, whereas fully or partially (at Asn91) glycosylated isoforms did; 2) high mannose type structures enhanced the hormone content; and 3) desialylation did not affect in vitro hormone synthesis. Evidence of a direct involvement in hormonosynthesis adds to the role of N-glycans in Tg function and opens the way to new mechanisms for regulation (e.g. TSH modulation of N-glycan) or alteration (e.g. Asn91 mutation) of thyroid hormone synthesis.

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This work was supported in part by the Association pour la Recherche en Biologie Cellulaire and presented in a preliminary form at the European Thyroid Association, Vienna, Austria, August 27-September 1, 1994. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a doctoral fellowship from the Institut National de la Santé et de la Recherche Médicale.