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Trends Immunol. 2012 Aug;33(8):406-12. doi: 10.1016/ Epub 2012 May 18.

Protecting a serial killer: pathways for perforin trafficking and self-defence ensure sequential target cell death.

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  • 1Peter MacCallum Cancer Centre, East Melbourne, 3002, Victoria, Australia.


Considerable progress has been made in understanding how cytotoxic lymphocytes use the highly toxic pore-forming protein perforin to eliminate dangerous cells, while remaining refractory to lysis. At least two mechanisms jointly preserve the killer cell: the C-terminal residues of perforin dictate its rapid export from the endoplasmic reticulum (ER), whose milieu otherwise favours pore formation; perforin is then stored in secretory granules whose acidity prevent its oligomerisation. Following exocytosis, perforin delivers the proapoptotic protease, granzyme B, into the target cell by disrupting its plasma membrane. Although the precise mechanism of perforin/granzyme synergy remains controversial, the recently defined crystal structure of the perforin monomer and cryo-electron microscopy (EM) of the entire pore suggest that passive transmembrane granzyme diffusion is the dominant proapoptotic mechanism.

Copyright © 2012 Elsevier Ltd. All rights reserved.

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