Thyroid functions of mouse cathepsins B, K, and L
Bianca Friedrichs, Carmen Tepel, Thomas Reinheckel, Jan Deussing, Kurt von Figura, Volker Herzog, Christoph Peters, Paul Saftig, Klaudia Brix
Bianca Friedrichs, Carmen Tepel, Thomas Reinheckel, Jan Deussing, Kurt von Figura, Volker Herzog, Christoph Peters, Paul Saftig, Klaudia Brix
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Thyroid functions of mouse cathepsins B, K, and L

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.

Authors

Bianca Friedrichs, Carmen Tepel, Thomas Reinheckel, Jan Deussing, Kurt von Figura, Volker Herzog, Christoph Peters, Paul Saftig, Klaudia Brix

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Redistribution of cathepsin B in thyroids of cathepsin K–/–, L–/–, or K–...
Redistribution of cathepsin B in thyroids of cathepsin K–/–, L–/–, or K–/–/L–/– mice. Confocal fluorescence micrographs of cryosections of thyroid glands from WT mice (a) or cathepsin-deficient mice of the indicated genotypes (b–f) were immunolabeled with antibodies against cathepsin B. Thyroids from cathepsin B–deficient mice were not stained (b and e), indicating specificity of antibody labeling. Cathepsin B was detected within endocytic vesicles of thyroid epithelial cells (arrows). In WT mice, cathepsin B was also located at the apical plasma membrane of epithelial cells (arrowheads, inset) and within the lumina of thyroid follicles (asterisks). Deficiencies in cathepsin K and/or cathepsin L resulted in a redistribution of cell surface–associated cathepsin B, since immunolabelings of the apical plasma membranes were no longer observed. Rather, immunofluorescence became detectable over the follicle lumina (asterisks), and it was enhanced when compared with the WTs. Note the presence of non-immunolabeled inclusions within the thyroid follicle lumina of cathepsin L–/– or K–/–/L–/– mice (open circles). Bars: 50 μm.