Perforin rapidly induces plasma membrane phospholipid flip-flop.

The cytotoxic cell granule secretory pathway is essential for host defense. This pathway is fundamentally a form of intracellular protein delivery where granule proteases (granzymes) from cytotoxic lymphocytes are thought to diffuse through barrel stave pores generated in the plasma membrane of the target cell by the pore forming protein perforin (PFN) and mediate apoptotic as well as additional biological effects. While recent electron microscopy and structural analyses indicate that recombinant PFN oligomerizes to form pores containing 20 monomers (20 nm) when applied to liposomal membranes, these pores are not observed by propidium iodide uptake in target cells.

Intracellular trafficking of perforin: to thwart a killer.

How do killer cells restrain perforin, the most potent toxin known to biologists, at its point of synthesis in the endoplasmic reticulum, where conditions are ideal for its activation? In this issue of Immunity, Brennan et al. (2011) study its trafficking, offering insights into protective mechanisms.