The role of thyroglobulin in thyroid hormonogenesis

Abstract

In humans, the thyroid hormones T3 and T4 are synthesized in the thyroid gland in a process that crucially involves the iodoglycoprotein thyroglobulin. The overall structure of thyroglobulin is conserved in all vertebrates. Upon thyroglobulin delivery from thyrocytes to the follicular lumen of the thyroid gland via the secretory pathway, multiple tyrosine residues can become iodinated to form mono-iodotyrosine (MIT) and/or di-iodotyrosine (DIT); however, selective tyrosine residues lead to preferential formation of T4 and T3 at distinct sites. T4 formation involves oxidative coupling between two DIT side chains, and de novo T3 formation involves coupling between an MIT donor and a DIT acceptor. Thyroid hormone synthesis is stimulated by TSH activating its receptor (TSHR), which upregulates the activity of many thyroid gene products involved in hormonogenesis. Additionally, TSH regulates post-translational changes in thyroglobulin that selectively enhance its capacity for T3 formation — this process is important in iodide deficiency and in Graves disease. 167 different mutations, many of which are newly discovered, are now known to exist in TG (encoding human thyroglobulin) that can lead to defective thyroid hormone synthesis, resulting in congenital hypothyroidism.

Key points

  • The first definitive evidence of a complete TG gene appears with the development of the vertebrates, and once appearing in evolution, the entire structure of thyroglobulin, as well as its ability to be secreted, has been retained thereafter.

  • The synthesis of T3 and T4 within thyroglobulin involves oxidative coupling between iodinated tyrosine residues on thyroglobulin.

  • The main T3-forming site within thyroglobulin couples a mono-iodotyrosine donor at the antepenultimate residue of one monomer with a di-iodotyrosine acceptor in the same residue of the apposed monomer within a dimer.

  • Post-translational modifications of thyroglobulin include phosphorylation for which the secretory pathway kinase FAM20C has been implicated.

  • TSH stimulation of thyrocytes promotes post-translational modifications that can alter thyroglobulin structure in a way that favours T3 formation upon iodination, whereas defects in TSH-mediated stimulation result in thyroglobulin with diminished capacity to form T3.

  • 167 TG mutations exist that can cause congenital hypothyroidism; although the disease is usually inherited as an autosomal recessive trait, patients with congenital hypothyroidism bearing monoallelic mutations of TG have recently been reported.

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Fig. 1: Regional structure and primary hormonogenic sites found within thyroglobulin.
Fig. 2: Overview of de novo thyroid hormone biosynthesis.
Fig. 3: Physiological enzymatic reactions involved in thyroid hormone synthesis.
Fig. 4: Thyroglobulin post-translational modifications.
Fig. 5: Mechanisms of de novo hormonogenesis at conserved sites on thyroglobulin.
Fig. 6: TSH regulation of thyroid hormone biosynthesis in thyroglobulin.

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Acknowledgements

The authors acknowledge the support of NIH grant R01 DK40344.

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Nature Reviews Endocrinology thanks X. DeDeken, J. Lado-Abeal and other anonymous reviewer(s) for their contribution to the peer review of this work.

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C.E.C., H.M.T. and P.A. researched data for the article and made a substantial contribution to discussion of content. C.E.C. and P.A. wrote, reviewed and/or edited the manuscript before submission.

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Correspondence to Peter Arvan.

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Glossary

Metamorphosis

An abrupt developmental change in the shape or form of an animal.

Endostyle

A longitudinal, ciliated, grooved organ located on the ventral wall of the pharynx of chordates that has functional equivalence to the vertebrate thyroid gland, among other functions.

Thyroid hormonogenic coupling reaction

A post-translational modification resulting in the physical transfer of a mono-iodotyrosine or di-iodotyrosine donor to a di-iodotyrosine acceptor within a protein.

Thyroglobulin short unique tail sequence

Refers to the final ~32 residues of the thyroglobulin sequence containing the antepenultimate tyrosine residue that can form T3 and is conserved throughout all vertebrates.

De novo T3 formation

Refers to the synthesis of T3 within the thyroglobulin polypeptide backbone that occurs as a result of the coupling of iodotyrosines.

Thyroglobulin non-hormonogenic tyrosine residues

Refers to the tyrosines within thyroglobulin that are not directly involved in thyroid hormone synthesis.

Haploinsufficiency

A condition that arises when there is a complete loss of function of one copy of a gene, and the remaining functional copy of the gene is not adequate to preserve normal function in a diploid organism.

Monoallelic mutations

Changes in the genetic sequence in one of two homologous alleles (paternal or maternal) of a single gene.

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Citterio, C.E., Targovnik, H.M. & Arvan, P. The role of thyroglobulin in thyroid hormonogenesis. Nat Rev Endocrinol 15, 323–338 (2019). https://doi.org/10.1038/s41574-019-0184-8

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