Vesicle Fusion Keeps Cells Moving

ReseaRch highlights

Nature Reviews Immunology | AoP, published online 18 june 2010; doi:10.1038/nri2810

T CELL RESPONSES Vesicle fusion keeps cells moving

Migrating cells adopt a polarized This indicated that SYT2 and SYTL5 also inhibited T cell chemotaxis morphology, characterized by function as negative and positive responses. By analysing the expression a leading-edge lamellipodia and a regulators of chemotaxis, respectively. of lysosome-associated membrane trailing-edge uropod, and move Screening other members of the protein 1 (LAMP1) on the surface through tissues by sequential adhe- SYT family, the authors identified of complement component C5a- sion and release steps. Understanding SYT7 as an additional positive regula- stimulated neutrophils, the authors the molecular mechanisms by which tor of chemotaxis. In time-lapse video confirmed that chemoattractants chemoattractants promote such microscopy studies, neutrophils from induce lysosome–cell membrane migration is an important goal for SYT7-deficient mice showed reduced fusion and found that this fusion immunologists and cell biologists. velocity, less prominent lamellipodia process was markedly inhibited in Now, Luster and colleagues show and dysregulated directionality in SYT7-deficient neutrophils. Finally, that members of the synaptotagmin response to the chemoattractant in confocal microscopy studies in (SYT) family, which regulate intra- N-formyl-methionyl-leucyl- which the intracellular localization of cellular vesicle trafficking and fusion, phenylalanine (fMLP). Furthermore, low-pH vesicles (such as lysosomes) are important for coordinating these SYT7-deficient mice showed impaired was visualized by use of a tracker dye, steps during leukocyte migration. neutrophil recruitment in an inflam- chemokine-treated SYT7-deficient Using a lentivirus-based RNA- matory model of gout; this was not due T cells showed higher accumulation of mediated interference (RNAi) to defective cytokine or chemokine labelled vesicles in the distal uropod approach to screen for genes involved production as peritoneal macrophages of the cell and showed difficulty in in chemotaxis, the authors identi- from wild-type and SYT7-deficient detaching from the substrate. fied several genes that affected mice produced This study has shown that regula- migratory similar levels of tion of vesicle trafficking and fusion responses of a interleukin-1β and is crucial for chemotaxis and has human T cell CXCL2. identified members of the SYT family lymphoma The identifica- as important regulators of leukocyte line to CXC- tion of a regula- migration. The authors speculate chemokine tory role for SYT that vesicle–membrane fusion could ligand 12 (CXCL12). family members facilitate the migration of immune Nine of these genes had not during chemotaxis sug- cells by delivering factors to the cell previously been linked to gested that vesicle fusion surface that promote detachment chemotaxis, including the could be important for from the underlying substrate. genes encoding SYT2 and directing cell migration. Yvonne Bordon a related protein, SYTL5. In support of this idea, Knockdown of Syt2 enhanced RNAi-mediated silencing ORIGINAL RESEARCH PAPER Colvin, R. A. et al. T cell migratory responses to of Rab27a and Rab3a Synaptotagmin-mediated vesicle fusion regulates cell migration. Nature Immunol. 11, CXCL12, but knockdown of (small GTPases involved 495–502 (2010) Sytl5 inhibited cell migration. in lysosome exocytosis)