Cathepsins (lysosomal proteases)

Cathepsins are a family of lysosomal proteases — predominantly cysteine proteases (cathepsins B, C, H, K, L, S, V, X/Z) but also aspartyl (cathepsins D, E) and serine types (cathepsins A, G) — that collectively execute the terminal degradation of proteins delivered by autophagy, endocytosis, and phagocytosis in the acidic lysosomal lumen. Beyond lysosomal digestion, cathepsins can be secreted to remodel the extracellular matrix (cathepsin K is the primary bone collagenase), and cytosolic leakage of cathepsins — particularly cathepsin B — can trigger the NLRP3 inflammasome and initiate apoptosis, a pathway termed lysosomal membrane permeabilisation. Cathepsin activity declines with ageing in part due to impaired lysosomal acidification and altered cystatin inhibitor balance, impairing protein quality control and contributing to accumulation of undegraded material in long-lived post-mitotic cells such as neurons.