When death starts with a caspase

When a cytotoxic lymphocyte delivers granzyme B to a target cell, current models emphasize that the enzyme induces apoptosis through a mitochondria-centered pathway, cleaving the proapoptotic Bcl-2 family member Bid to cause mitochondrial permeabilization. On page 875, Metkar et al. overturn this view, showing that in the dominant pathway granzyme B begins by processing procaspase-3, whereas mitochondria are secondary components that amplify the signal once caspase-3 has been activated. The work adds to recent evidence that caspases can initiate apoptosis, whereas mitochondria serve as signal amplifiers.

The authors used a variety of strategies to avoid common pitfalls during granzyme- mediated apoptosis assays. In past assays, uncomplexed granzyme B was added to cell extracts. Granzyme B in the new assays was delivered into cells using adenovirus particles, and was presented in...