Arf6: a new player in FcgammaRIIIA lymphocyte-mediated cytotoxicity.
The activation of phosphoinositide metabolism represents a critical step in the signaling pathways leading to the activation of cytolytic machinery, but its regulation is partially understood. We report here that the stimulation of the low-affinity receptor for immunoglobulin G (IgG) (FcgammaRIIIA, CD16) on primary human natural killer (NK) cells induces a phosphatidylinositol 3-kinase (PI3K)-dependent activation of the small G protein Arf6. We first demonstrate a functional role for Arf6-dependent signals in the activation of the antibody-dependent cellular cytotoxicity (ADCC) attributable to the control of secretion of lytic granule content. We also show that Arf6 couples CD16 to the lipid-modifying enzymes phosphatidylinositol4phosphate 5-kinase type I alpha (PI5KIalpha) and phospholipase D (PLD) that are involved in the control of granule secretion; Arf6, but not Rho family small G proteins RhoA and Rac1, is required for receptor-induced PI5KIalpha membrane targeting as well as for PI5KIalpha and PLD activation. Our findings suggest that Arf6 plays a crucial role in the generation of a phosphatidylinositol4,5-bisphosphate (PIP2) plasma membrane pool required for cytolytic granule-mediated target cell killing.
Galandrini
Ricciarda
R
Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci-Bolognetti, University La Sapienza, viale Regina Elena, 324, 00161 Rome, Italy. ricciarda.galandrini@uniroma1.it
Micucci
Federica
F
Tassi
Ilaria
I
Cifone
Maria Grazia
MG
Cinque
Benedetta
B
Piccoli
Mario
M
Frati
Luigi
L
Santoni
Angela
A
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D010739:Phospholipase D / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism*; D022142:Secretory Vesicles / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors; D019869:Phosphatidylinositol 3-Kinases; D019269:Phosphatidylinositol 4,5-Diphosphate; D010739:Phospholipase D; D017853:Phosphotransferases (Alcohol Group Acceptor); D017452:Receptors, IgG; C496124:FCGR3A protein, human; C020077:1-phosphatidylinositol-4-phosphate 5-kinase; C000715348:ARF6 protein, human