Caspase-8 induces lysosome-associated cell death in cancer cells

Abstract Caspase-8, a well-characterized initiator of apoptosis, has also been found to play non-apoptotic roles in cells. Here we reveal that caspase-8 can induce cell death in a special way, which does not depend on caspases activation and mitochondrial initiation. Instead, we prove that caspase-8 can cause lysosomal deacidification and thus lysosomal membrane permeabilization. V-ATPase is a multi-subunit proton pump that acidifies the lumen of lysosome. Our results demonstrate that caspase-8 can bind to V0 domain of lysosomal V-ATPase, but not V1 domain, to block the assembly of functional V-ATPase and alkalinize lysosomes. We further demonstrate that C-terminal of caspase-8 is mainly responsible for the interaction with V-ATPase and can suffice to inhibit survival of cancer cells. Interestingly, regardless of the protein level, it is the expression rate of caspase-8 that is the major cause to cell death. Taken together, we identify a previously unrevealed caspase-8-mediated cell death pathway different form typical apoptosis, which could render caspase-8 a particular physiological function and may be potentially applied in treatments for apoptosis-resistant cancers.