cathepsins

Cathepsins are a broad family of proteolytic enzymes that function primarily within the acidic environment of lysosomes. Most members are cysteine proteases, but the family also includes aspartic proteases and, in at least one case, a serine protease. They are typically synthesized as inactive proenzymes and activated by proteolytic processing under acidic conditions, enabling controlled protein degradation inside cells and in secretory pathways.

Major members include B, C, D, L, S and K. Cathepsin B and L drive general protein turnover; cathepsin D and E are lysosomal aspartic proteases; cathepsin K is specialized for collagen degradation in osteoclasts. Cathepsin S participates in antigen processing in immune cells, and cathepsin G is a serine protease found in neutrophils. Tissue distribution and substrate specificities vary among members, reflecting diverse physiological roles.

Functions extend beyond intracellular digestion. In the immune system, cathepsins contribute to the generation of peptide fragments for presentation by MHC class II molecules. In extracellular matrix remodeling, cathepsin K degrades collagen and other matrix components, supporting bone resorption and, in some cancers, tumor invasion. Dysregulated cathepsin activity has been linked to inflammatory and neurodegenerative diseases, and individual enzymes may contribute to pathologic tissue remodeling, angiogenesis, or metastasis.

Regulation and localization are tightly controlled. Cathepsin activity depends on lysosomal pH, subcellular trafficking, and endogenous inhibitors such as cystatins. Activation generally occurs via proteolytic processing in endolysosomal compartments, with secretion observed in inflammatory or diseased states.

Clinical relevance is underscored by associations between altered cathepsin expression or activity and cancer, osteoporosis, arthritis, and neurodegenerative disorders. Cathepsin inhibitors have been explored as therapies, but clinical development has faced safety and efficacy challenges for several targets.