Abstract
Cathepsin S (catS), which is expressed in normal human keratinocytes and localized close to the dermal-epidermal junction (DEJ) degrades some of major basement membrane (BM) constituents. Among them, catS readily hydrolyzed in a time and dose dependent manner human nidogen-1 (nid-1) and nidogen-2, which are key proteins in the BM structure. CatS preferentially cleaved nid-1 at both acid and neutral pH. Hydrolysis of nid-1 was hampered in murine ctss −/− spleen lysates pretreated with inhibitors of other classes of proteases. Nid-1 was cleaved within its G2 and G3 globular domains that are both involved in interactions with other BM components. Binding assays with soluble and immobilized ligands indicated that catS altered the formation of complexes between nid-1 and other BM components. Assuming that the cleavage of nid-1 impairs its ability to crosslink with BM partners and perturbs the viscoelastic properties of BM matrix, these data indicate that catS may participate in BM proteolysis, in addition to already identified proteases.
Highlights
The basement membrane (BM) is a continuous sheet of specialized extracellular matrix (ECM) that regulates tissue morphogenesis and cell functions like differentiation, migration and survival by providing the scaffolding that maintains normal tissue architecture during regeneration and growth [1]
CatB was found in the vesicles of the perinuclear region of proliferative keratinocytes, while catB was more broadly distributed throughout the upper layers
We identified the extracellular cathepsins produced by human keratinocytes, prior to evaluating their role in BM hydrolysis
Summary
The basement membrane (BM) is a continuous sheet of specialized extracellular matrix (ECM) that regulates tissue morphogenesis and cell functions like differentiation, migration and survival by providing the scaffolding that maintains normal tissue architecture during regeneration and growth [1]. Nidogens are ubiquitous BM proteins, with nidogen-1 (nid-1) being more abundant in mammals while the pattern of nidogen-2 (nid-2) distribution is distinct from nid-1. Both nidogens play a central role in the supramolecular organization of the basal laminae in tissues such as skin, muscle, lung and the nervous system [4]. Nid-1 consists of a single polypeptide chain (150 kDa) that forms three globular domains, G1 (with an apparent molecular mass of 30–35 kDa), G2 (31 kDa), and G3 (44 kDa), separated from each other by either a flexible, protease-sensitive linker (G1, G2) or a longer rigid rod-like domain (G2, G3)
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