Cytolytic granules supply Ca2+ for their own exocytosis via NAADP and resident two-pore channels

Abstract

When cytotoxic T-lymphocytes (CTLs) kill infected or cancerous cells they secrete cytolytic proteins (perforin and granzymes) into the target cell. These "death factors" arepre-stored in cytolytic granules within the CTL until an increase in the intracellular Ca2+ drives granule exocytosis. However, not all sources of Ca2+ stimulate exocytosis: we have recently demonstrated that it is the cytolytic granules themselves that are the source of the Ca2+that most efficiently drives their own exocytosis; release of Ca2+ from thegranules is only activated by the Ca2+-mobilizing messenger NAADP (nicotinic acid adeninedinucleotide phosphate) that acts upon target two-pore channels (TPCs) present on the granules. That NAADP is a unique stimulus of exocytosis may be of fundamental importance notonly to immunology but to cell biology in general. © 2013 Landes Bioscience.