Interferon-gamma listericidal action is mediated by novel Rab5a functions at the phagosomal environment.
Control and clearance of Listeria monocytogenes infection is an interferon-gamma-dependent process. The listericidal mechanism of action involves activation of NADPH oxidase and inducible nitric-oxide synthase to produce reactive oxygen and nitrogen intermediate radicals, respectively. Recently, we have described in a nonpathogenic model of L. monocytogenes (hemolysin negative mutant strain) that the interferon-gamma-inducible GTPase Rab5a contributed to Listeria destruction in resting macrophages. Here, we report in a pathogenic model of L. monocytogenes (hemolysin-positive strain) that Rab5a plays a central role in Listeria destruction induced by interferon-gamma and within the phagosomal environment. These findings reveal the importance of Rab5a as the responsible factor mediating the listericidal action of interferon-gamma. Active Rab5a causes remodeling of the phagosomal environment, facilitates the translocation of Rac2 to LM phagosomes, and regulates the activity of this GTPase. Rac2 activation and translocation governs the phagocyte NADPH oxidase activity and the consequent reactive oxygen intermediate production that leads to killing of the pathogen.
Centro de Biologia Molecular "Severo Ochoa," Universidad Autónoma de Madrid, 28049 Madrid, Spain.
A
A
Prada-Delgado
E
E
Carrasco-Marin
G M
GM
Bokoch
C
C
Alvarez-Dominguez
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology*; D008089:Listeria monocytogenes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D019255:NADPH Oxidases / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009584:Nitrogen / Q000378:metabolism; D010587:Phagocytosis; D010588:Phagosomes / Q000378:metabolism*; D011233:Precipitin Tests; D021381:Protein Transport; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D019255:NADPH Oxidases; D020558:GTP Phosphohydrolases; D020696:rab5 GTP-Binding Proteins; D009584:Nitrogen