Messenger et al. show that exosome secretion in cancer cells is Ca2+-stimulated and dependent on Ca2+-bound Munc13-4. Munc13-4, a late endosome priming factor, acts via a Rab11-dependent pathway to prepare multivesicular endosomes for exocytosis. These results indicate that Munc13-4 plays a central role in exosome release in cancer cells.

Munc13-4, a Ca2+-dependent SNARE/phospholipid-binding protein on secretory granules (SGs), functions as a Ca2+ sensor for SG exocytosis and SG-SG fusion. SG-SG fusion plus fusion with recycling endosomes generates large (>2.4 μm) Munc13-4+/Rab7+/Rab11+ exocytic vacuoles. The results provide insights into multigranular compound exocytosis.

Maturation is an important process by which dendritic cells (DC) develop the potent antigen-presentation capacity necessary for efficient activation of adaptive immunity. Here, we have investigated the ability of lipoteichoic acid (LTA) and muramyl dipeptide (MDP; the minimal structural unit of peptidoglycan with immunostimulating activity) to induce maturation of human immature DC (iDC), derived from peripheral blood CD14-positive cells, and the production of proinflammatory cytokines. Exposure of iDC to staphylococcal LTA (StLTA) at 1 or 10 microg/ml or MDP at 0.1 or 1 microg/ml alone had little effect on the expression of CD80 and CD83, with a minor increase in expression of CD86, all of which are indicative of cell surface markers for maturation. However, there was a synergistic expression of these molecules when iDC were stimulated with StLTA and MDP together. It is interesting that selective induction of MHC Class II expression was observed during the DC maturation, only when costimulated with LTA plus MDP, and Escherichia coli LPS induced dramatic expression of MHC Classes I and II. Endocytosis assay using Dextran-FITC showed that costimulation with StLTA and MDP attenuated the endocytic capacity of the DC, which is a typical phenomenon of DC maturation. Concomitantly, increased expression of DEC-205, but decreased expression of CD206, was observed under the same costimulating condition. Furthermore, ELISA showed that secretions of TNF-alpha and IL-12 p40, but not IL-10, were induced in iDC by the costimulation. These results suggest that StLTA and MDP synergistically induce maturation and activation of human DC.

No abstract

No abstract