Endocytosing the death sentence

A series of recent studies have suggested that endocytosis of the mannose-6-phosphate receptor (MPR) might play a critical role in delivering the death signal to cells targeted for destruction by the immune system (for review see Barry and Bleackley, 2002). These studies have raised a number of controversial issues regarding the trafficking of proteins from the plasma membrane of the target cell to their substrates in the cytosol. In this issue, Trapani and colleagues examine the death of cells in which endocytosis of the MPR is blocked and show that the death signal is delivered effectively in the absence of MPR endocytosis (Trapani et al., 2002, this issue). How then is the death sentence delivered?