title: Cathepsin B launches an apoptotic exit effort upon cell death-associated disruption of lysosomes.
abstract: The release of cathepsin proteases from disrupted lysosomes results in lethal cellular autodigestion. Lysosomal disruption-related cell death is highly variable, showing both apoptotic and necrotic outcomes. As the substrate spectrum of lysosomal proteases encompasses the apoptosis-regulating proteins of the Bcl-2 family, their degradation could influence the cell death outcome upon lysosomal disruption. We used Förster resonance energy transfer (FRET)-based biosensors to image the real-time degradation of the Bcl-2-family members, Bcl-xl, Bax and Bid, in living cells undergoing lysosomal lysis and identified an early chain of proteolytic events, initiated by the release of cathepsin B, which directs cells toward apoptosis. In this apoptotic exit strategy, cathepsin B's proteolytic activity results in apoptosis-inducing Bid and removes apoptosis-preventing Bcl-xl. Cathepsin B furthermore appears to degrade a cystein protease that would otherwise have eliminated apoptosis-supporting Bax, indirectly keeping cellular levels of the Bax protein up. The concerted effort of these three early events shifts the balance of cell fate away from necrosis and toward apoptosis.
authors.affiliation: Laboratory for Molecular and Cellular Systems, Institute of Neuropathology, University Medical Center Göttingen , Göttingen, Germany.
authors.forename: M A G
authors.initials: MA
authors.lastname: de Castro
authors.affiliation: Laboratory for Molecular and Cellular Systems, Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany; Clinical Optical Microscopy, Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Bunt
authors.affiliation: Laboratory for Molecular and Cellular Systems, Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany; Centre for Nanoscale Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: F S
authors.initials: FS
authors.lastname: Wouters