Synaptotagmin II negatively regulates Ca2+-triggered exocytosis of lysosomes in mast cells

Synaptotagmins (Syts) I and II are believed to act as Ca2+ sensors in the c ontrol of neurotransmission. Here we demonstrate that mast cells express Sy t II in their lysosomal fraction. We further show that activation of mast c ells by either aggregation of Fc epsilon RI or by Ca2+ ionophores results i n exocytosis of lysosomes, in addition to the well documented exocytosis of their secretory granules. Syt II directly regulates lysosomal exocytosis, whereby overexpression of Syt II inhibited Ca2+-triggered release of the ly sosomal processed form of cathepsin D, whereas suppression of Syt II expres sion markedly potentiated this release. These findings provide evidence for a novel function of Syt II in negatively regulating Ca2+-triggered exocyto sis of lysosomes, and suggest that Syt II-regulated secretion from lysosome s may play an important role in mast cell biology.