ISSN 1470-3947 (print)
ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology

Published by BioScientifica
Endocrine Abstracts (2007) 14 S7.3 
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Thyroglobulin deposition and cathepsin-dependent Tg mobilization

Klaudia Brix1, Sasa Jenko-Kokalj2, Dusan Turk2, Dieter Brömme3, Nicole Kühl1 & Silvia Jordans1

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Thyroid hormones thyroxine and triiodothyronine are essential for development, growth and metabolism. The prohormone thyroglobulin (Tg) is stored in high concentrations and in covalently cross-linked form within the lumen of thyroid follicles. Thyroid hormones are liberated from Tg in a regulated manner in that TSH triggers the secretion of lysosomal enzymes into the extracellular follicle lumen where they solubilize covalently cross-linked Tg and liberate thyroxine by partial Tg degradation. Using mice deficient in cysteine cathepsins B, K, and/or L, we showed that liberation of thyroid hormones from within Tg is based on the concerted action of a protease network. Cathepsins B and L are key players in conversion of cross-linked Tg-globules to soluble Tg. Moreover, assessment of thyroid morphology and serum thyroxine levels of cathepsin K- and L-deficient mice revealed impaired mobilization of Tg. The respective mice exhibited a phenotype reminiscent of hypothyroidism, proving the importance of cathepsins K and L for the liberation of thyroid hormones. Tg storage and Tg mobilization both occur extracellularly. Hence, the conditions for Tg processing are non-favorable for the proteolytic activity of lysosomal cysteine cathepsins. Therefore, we set-up an in vitro degradation assay that simulates the in vivo situation. Indeed, in such assays the cysteine cathepsins B, K, L and S were able to partially degrade their natural substrate Tg even at neutral pH and oxidizing conditions. Analysis of the cleavage sites of cysteine cathepsins under extracellular conditions revealed that sub-cellular and sub-follicular localization of the proteases as well as the timing of proteolysis are crucial steps in the regulation of thyroid hormone liberation from Tg. Any interference with the delicate protease network in the thyroid may result in impaired function.

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