Thyroid Cathepsin K: Roles in Physiology and Thyroid Disease

Abstract

The human genome encodes 11 cysteine cathepsins belonging to the papain-like family of cysteine peptidases that are known predominantly as endo-lysosomal enzymes. However, it is now understood that the functions and activities of cysteine cathepsins are not limited to endo-lysosomal compartments, as they are also active in the peri-and extracellular space. The thyroid gland is an endocrine organ where such intra-and extracellular proteolytic activities are required to solubilize the prohormone thyroglobulin from its luminal, covalently cross-linked storage forms for subsequent processing into smaller protein fragments and thyroid hormone liberation. Cathepsin K has been identified as one of the cysteine cathepsins with a crucial role in thyroglobulin processing. However, cathepsin K has mainly been a key focus of attention in the last few years because of its high expression in osteoclasts and due to its essential role as collagenase and elastase important for bone remodelling. Besides its remarkable function as an endopeptidase acting on highmolecular mass, covalently cross-linked extracellular substrates such as type I collagen, elastin or thyroglobulin, cathepsin K is also one of the very few proteolytic enzymes that is able to directly liberate thyroxine from thyroglobulin fragments by exopeptidase action. Thus, thyroid cathepsin K is now accepted as a cysteine peptidase with a vital role in liberation of thyroid hormones, which in turn are essential for homoeostasis by triggering a number of important biological processes, ranging from growth and brain development in young vertebrates to tissue remodelling events during morphogenesis or wound healing, as well as control of metabolic pathways and thermoregulation in adults. This review focuses on thyroid cathepsin K and will discuss how localization and trafficking within thyroid epithelial cells explain its thyroid-specific functions. The effects of targeted cathepsin K gene ablation will be summarized from the perspective of the thyroid gland, and we will propose potential consequences of short-and long-term inhibition of thyroid cathepsin K activity for the main thyroid hormone target tissues, namely bone, cardiovascular and immune systems, intestine, and the central nervous system, in addition to the thyroid gland itself.

Trace Amine-Associated Receptor 1 Localization at the Apical Plasma Membrane Domain of Fisher Rat Thyroid Epithelial Cells Is Confined to Cilia

“…We determine that the ciliated apical plasma membrane domain of thyroid epithelial cells bears critical functions in that it harbors the means for formation of iodothyronines during TH generation while also serving as a platform of initial cysteine cathepsin-mediated thyroglobulin processing for TH liberation [16,17,18,19]. Hence, the localization of Taar1 in the primary cilium at the apical plasma membrane domain of thyroid epithelial cells in vitro and in situ provides the source for novel hypotheses in thyroid cell biology.…”

“…Thyronamines can, in principle, be generated by extra- or intrathyroidal means which involve deiodination and decarboxylation of iodothyronines generated by the degradation of thyroglobulin within the thyroid follicles ( a ). Thyroglobulin degradation is mediated by cysteine cathepsins B, K, L, and/or S, starting in the extracellular follicle lumen and continuing in the compartments of the endocytic pathway [17,19]. If generated by extrathyroidal means, thyronamines need to be imported by unknown transporter molecules (black boxes).…”

“…The prohormone thyroglobulin is synthesized by thyrocytes and, upon secretion and iodination, is stored within the lumen. TSH binds to the basolateral TSH receptor - the best-studied thyroidal GPCR - thereby triggering the sequential proteolytic processing of thyroglobulin mediated by cysteine cathepsins that act in the pericellular space close to the apical cell surface, including cilia, and within endocytic compartments of thyroid epithelial cells, resulting in thyroglobulin utilization for TH liberation [16,17,18,19]. …”

Proteolysis mediated by cysteine cathepsins and legumain—recent advances and cell biological challenges

“…In comparison to the limited variety of biochemical cleavage mechanisms, there is an impressively diverse cellular and extracellular repertoire of physiological substrates, as well as endogenous protease inhibitors which are called into action for the regulation of proteolysis in response to cellular conditions (Andrade et al 2011;Brix et al 2013;Dauth et al 2011a;Turk et al 2008). Locally and temporally controlled protease activities are already seen very early in life, such as the acrosomal process during fertilization of the egg cell (Mao and Yang 2013).…”

“…& Fifth, there is transcytosis, i.e., a pathway typical for epithelial and endothelial cells in which endocytic uptake of molecules happens at one pole of the epithelium and their secretory release at the opposite side of the epithelium is made possible, with the cargo strictly by-passing endolysosomal hydrolases (Romagnoli and Herzog 1991). & Finally, retrieval of proteolytically active endo-lysosomal enzymes into retrograde transport vesicles is observed in several specialized cell types, namely macrophages and other cells of the immune system, as well as in osteoclasts and thyroid epithelial cells (Andrews 2000;Blott and Griffiths 2002;Brix et al 1996Brix et al , 2008Dauth et al 2011a;Linke et al 2002a, b;Luzio et al 2014). In this way, cells may reroute the entire or selected contents of their endo-lysosomes directly to the plasma membrane for secretion into the extracellular space.…”