[Signal transduction by Rac small G proteins in phagocytes].
Rac1 and Rac2 are 92% homologous cytosolic small GTPase proteins. Both Rac1 and Rac2 have been implicated with NADPH oxidase activation in vitro, however, Rac2 is largely predominant in human phagocytes. NADPH oxidase is a plasma membrane enzyme of phagocytes, generating superoxide anions which serve as bactericidal agents. Activation of this multimolecular enzyme, minimally requires assembly at the membrane with flavocytochrome b258 of cytosolic components p47phox, p67phox and Rac proteins. Using the yeast two hybrid system, we provide data demonstrating in vivo interactions between human p47phox, p67phox, and Rac proteins. Rac proteins interact with p67phox in a GTP-dependent manner, but do not interact with p47phox. Moreover, Rac effector site mutants which are known to be inactive in NADPH oxidase lose their interaction with p67phox. Finally, we observe that p67phox interacts six fold better with Rac2 than with Rac1. We also show a strong intracellular interaction between p47phox and p67phox. These results indicate that activated Rac, and particularly Rac2, can regulate superoxide production by NADPH oxidase of phagocytic cells through direct interaction with p67phox subunit. Recently published data suggest that Rac proteins could transduce mitogenic signals in non-phagocytic cells through superoxide production by a phagocytic-related NADPH oxidase enzymatic system which remains to be determined. NADPH oxidase regulation by Rac proteins in phagocytes could then be used as a model to understand the molecular mechanisms underlying Rac functions in various cell types.
Dorseuil
O
O
INSERM U257, Institut Cochin de Génétique Moléculaire 24, Paris.
Gacon
G
G
D019204:GTP-Binding Proteins / Q000378:metabolism*; D066298:In Vitro Techniques; D007249:Inflammation / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D010586:Phagocytes / Q000378:metabolism*; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins
D019255:NADPH Oxidases; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins
Signalisation par les petites protéines G de la famille Rac dans les phagocytes.