Synaptotagmin-mediated vesicle fusion regulates cell migration.
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.
Colvin
Richard A
RA
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.
Means
Terry K
TK
Diefenbach
Thomas J
TJ
Moita
Luis F
LF
Friday
Robert P
RP
Sever
Sanja
S
Campanella
Gabriele S V
GS
Abrazinski
Tabitha
T
Manice
Lindsay A
LA
Moita
Catarina
C
Andrews
Norma W
NW
Wu
Dianqing
D
Hacohen
Nir
N
Luster
Andrew D
AD
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
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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