Thyroid functions of mouse cathepsins B, K, and L


Friedrichs, B; Tepel, C; Reinheckel, T; Deussing, J; von Figura, K; Herzog, V; Peters, C; Saftig, P; Brix, K; (2003) Thyroid functions of mouse cathepsins B, K, and L. The Journal of clinical investigation, 111 (11). pp. 1733-45. ISSN 0021-9738 DOI: 10.1172/JCI15990

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Abstract

Thyroid function depends on processing of the prohormone thyroglobulin by sequential proteolytic events. From in vitro analysis it is known that cysteine proteinases mediate proteolytic processing of thyroglobulin. Here, we have analyzed mice with deficiencies in cathepsins B, K, L, B and K, or K and L in order to investigate which of the cysteine proteinases is most important for proteolytic processing of thyroglobulin in vivo. Immunolabeling demonstrated a rearrangement of the endocytic system and a redistribution of extracellularly located enzymes in thyroids of cathepsin-deficient mice. Cathepsin L was upregulated in thyroids of cathepsin K(-/-) or B(-/-)/K(-/-) mice, suggesting a compensation of cathepsin L for cathepsin K deficiency. Impaired proteolysis resulted in the persistence of thyroglobulin in the thyroids of mice with deficiencies in cathepsin B or L. The typical multilayered appearance of extracellularly stored thyroglobulin was retained in cathepsin K(-/-) mice only. These results suggest that cathepsins B and L are involved in the solubilization of thyroglobulin from its covalently cross-linked storage form. Cathepsin K(-/-)/L(-/-) mice had significantly reduced levels of free thyroxine, indicating that utilization of luminal thyroglobulin for thyroxine liberation is mediated by a combinatory action of cathepsins K and L.

Item Type: Article
Keywords: Animals, Cathepsin B/genetics/*metabolism, Cathepsins/genetics/*metabolism, Cysteine Endopeptidases, Endocytosis, Genotype, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Confocal, Models, Biological, Mutation, Thyroglobulin/metabolism, Thyroid Gland/*metabolism, Thyroxine/blood/metabolism, Time Factors, Up-Regulation, Animals, Cathepsin B, genetics, metabolism, Cathepsins, genetics, metabolism, Cysteine Endopeptidases, Endocytosis, Genotype, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Confocal, Models, Biological, Mutation, Thyroglobulin, metabolism, Thyroid Gland, metabolism, Thyroxine, blood, metabolism, Time Factors, Up-Regulation
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
PubMed ID: 12782676
Web of Science ID: 183313400017
URI: http://researchonline.lshtm.ac.uk/id/eprint/7470

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