title: Synaptotagmin-mediated vesicle fusion regulates cell migration.
abstract: Chemokines and other chemoattractants direct leukocyte migration and are essential for the development and delivery of immune and inflammatory responses. To probe the molecular mechanisms that underlie chemoattractant-guided migration, we did an RNA-mediated interference screen that identified several members of the synaptotagmin family of calcium-sensing vesicle-fusion proteins as mediators of cell migration: SYT7 and SYTL5 were positive regulators of chemotaxis, whereas SYT2 was a negative regulator of chemotaxis. SYT7-deficient leukocytes showed less migration in vitro and in a gout model in vivo. Chemoattractant-induced calcium-dependent lysosomal fusion was impaired in SYT7-deficient neutrophils. In a chemokine gradient, SYT7-deficient lymphocytes accumulated lysosomes in their uropods and had impaired uropod release. Our data identify a molecular pathway required for chemotaxis that links chemoattractant-induced calcium flux to exocytosis and uropod release.
authors.affiliation: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Colvin
authors.forename: Terry K
authors.initials: TK
authors.lastname: Means
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Diefenbach
authors.forename: Luis F
authors.initials: LF
authors.lastname: Moita
authors.forename: Robert P
authors.initials: RP
authors.lastname: Friday
authors.forename: Sanja
authors.initials: S
authors.lastname: Sever
authors.forename: Gabriele S V
authors.initials: GS
authors.lastname: Campanella
authors.forename: Tabitha
authors.initials: T
authors.lastname: Abrazinski
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Manice
authors.forename: Catarina
authors.initials: C
authors.lastname: Moita
authors.forename: Norma W
authors.initials: NW
authors.lastname: Andrews
authors.forename: Dianqing
authors.initials: D
authors.lastname: Wu
authors.forename: Nir
authors.initials: N
authors.lastname: Hacohen
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Luster
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D054377:Chemokine CXCL12 / Q000378:metabolism; D002633:Chemotaxis; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D019718:Receptors, CXCR4 / Q000378:metabolism; D050861:Synaptotagmin II / Q000378:metabolism; D050857:Synaptotagmins / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D050861:Synaptotagmin II; C494263:Syt2 protein, mouse; C494296:Syt5 protein, mouse; C494303:Syt7 protein, mouse; D050857:Synaptotagmins
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