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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3665-3674.
Prepublished online as a Blood First Edition Paper on January 18, 2008; DOI 10.1182/blood-2007-07-103309.
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Submitted July 25, 2007
Accepted January 11, 2008
VAMP-8 segregates mast cell preformed mediator exocytosis from cytokine trafficking pathways
Neeraj Tiwari, Cheng-Chun Wang, Cristiana Brochetta, Gou Ke, Francesca Vita, Zeng Qi, Juan Rivera, Maria Rosa Soranzo, Giuliano Zabucchi, Wanjin Hong, and Ulrich Blank*
Inserm U699, Paris, France
Membrane Biology Laboratory, Institute of Molecular and Cellular Biology, Singapore, Singapore
Faculte de Medecine, Universite Paris 7-Denis Diderot, Site Xavier Bichat, Paris, France
Department of Physiology and Pathology, University of Trieste, Trieste, Italy
Laboratory of Immune Cell Signaling, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, United States
* Corresponding author; email: ublank{at}bichat.inserm.fr.
Inflammatory responses by mast cells are characterized by massive exocytosis of prestored granular mediators followed by cytokine/chemokine release. The vesicular trafficking mechanisms involved remain poorly understood. Vesicular Associated Membrane Protein-8 (VAMP-8), a member of the v-SNARE family of fusion proteins initially characterized in endosomal and endosomal-lysosomal fusion may also function in regulated exocytosis. Here we show that in bone marrow derived mast cells (BMMCs) VAMP-8 partially colocalized with secretory granules and redistributed upon stimulation. This was associated with increased SNARE complex formation with the target t-SNAREs, SNAP-23 and syntaxin-4. VAMP-8-deficient BMMCs exhibited a markedly reduced degranulation response after IgE+antigen-, thapsigargin- or ionomycin-induced stimulation. VAMP-8-deficient mice also showed reduced plasma histamine levels in passive systemic anaphylaxis experiments, while cytokine/chemokine release was not affected. Unprocessed TNF accumulated at the plasma membrane where it colocalized with a VAMP-3-positive vesicular compartment but not with VAMP-8. The findings demonstrate that VAMP-8 segregates secretory lysosomal granules exocytosis in mast cells from cytokine/chemokine molecular trafficking pathways.
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