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Synaptotagmin XI Regulates Phagocytosis and Cytokine Secretion in Macrophages

Synaptotagmin XI Regulates Phagocytosis and Cytokine Secretion in Macrophages Guillermo Arango Duque*,†, Mitsunori Fukuda‡ and Albert Descoteaux*,† + Author Affiliations *Institut National de la Recherche Scientifique–Institut Armand-Frappier, Laval, Quebec H7V 1B7, Canada; †Centre for Host-Parasite Interactions, Laval, Quebec H7V 1B7, Canada; and ‡Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan Address correspondence and reprint requests to Dr. Albert Descoteaux, Institut National de la Recherche Scientifique–Institut Armand-Frappier, 531 boulevard des Prairies, Laval, QC, Canada H7V 1B7. E-mail address: [e-mail] Abstract Synaptotagmins (Syts) are a group of type I membrane proteins that regulate vesicle docking and fusion in processes such as exocytosis and phagocytosis. All Syts possess a single transmembrane domain, and two conserved tandem Ca2+-binding C2 domains. However, Syts IV and XI possess a conserved serine in their C2A domain that precludes these Syts from binding Ca2+ and phospholipids, and from mediating vesicle fusion. Given the importance of vesicular trafficking in macrophages, we investigated the role of Syt XI in cytokine secretion and phagocytosis. We demonstrated that Syt XI is expressed in murine macrophages, localized in recycling endosomes, lysosomes, and recruited to phagosomes. Syt XI had a direct effect on phagocytosis and on the secretion of TNF and IL-6. Whereas small interfering RNA–mediated knockdown of Syt XI potentiated secretion of these cytokines and particle uptake, overexpression of an Syt XI construct suppressed these processes. In addition, Syt XI knockdown led to decreased recruitment of gp91phox and lysosomal-associated membrane protein–1 to phagosomes, suggesting attenuated microbicidal activity. Remarkably, knockdown of Syt XI ensued in enhanced bacterial survival. Our data reveal a novel role for Syt XI as a regulator of cytokine secretion, particle uptake, and macrophage microbicidal activity.