How do cells limit lysosomal enzyme leakage

Cells limit lysosomal enzyme leakage by using protective membranes, acid-dependent enzyme activity, chaperone proteins, and repair systems that quickly neutralize or reseal lysosomal leaks.

Protective mechanisms

• Membrane barrier: Lysosomal membrane is enriched with lysosome-associated membrane proteins (LAMPs) that shield the inner membrane from proteases.
• pH dependence: Enzymes only function well in acidic pH. If leaked into neutral cytosol, their activity is much lower.
• Chaperones and inhibitors: Cytosolic protease inhibitors (cystatins, serpins) can block cathepsins that escape.
• Membrane repair: ESCRT machinery and lysophagy (autophagy of damaged lysosomes) remove leaky lysosomes.
• Stress response: Heat shock proteins stabilize membranes and help refold proteins under stress.

These measures prevent small leaks from triggering full autolysis and maintain cell survival unless stress is overwhelming.