Lysosomal dysfunction by inhibition of cathepsins B and L causes cell death.

In the macroautophagy pathway, impaired organelles are enclosed by a phagophore or isolation-membrane (IM), expansion of which gives rise to the autophagosome, a double-membrane vacuole that engulfs cellular components. Subsequently, the autophagosome fuses with lysosomes, in which lysosomal cathepsins, i.e. cathepsin B, D, L, etc. play a key role to allow normal function of the lysosome. Fusion of autophagosomes with lysosomes forms autolysosomes, playing a role in the degradation of cytoplasmic organelles. Inhibition of cathepsins B and L resulted in the accumulation of abnormal unprocessed cathepsins (pro-cathepsins) in the lysosomes. Abnormal accumulation of pro-cathepsins in the lysosomes leads to impaired autophagic process, especially fusion with autophagosomes, resulting in enlarged lysosomes. This lysosomal dysfunction indicates the phenomenon manifesting in lysosomal storage, finally inducing cell death by the activation of caspases.