title: Nox2 and Rac1 regulate H2O2-dependent recruitment of TRAF6 to endosomal interleukin-1 receptor complexes.
abstract: Reactive oxygen species (ROS) generated by NADPH oxidases (Nox) have been implicated in the regulation of signal transduction. However, the cellular mechanisms that link Nox activation with plasma membrane receptor signaling remain poorly defined. We have found that Nox2-derived ROS influence the formation of an active interleukin-1 (IL-1) receptor complex in the endosomal compartment by directing the H2O2-dependent binding of TRAF6 to the IL-1R1/MyD88 complex. Clearance of both superoxide and H2O2 from within the endosomal compartment significantly abrogated IL-1beta-dependent IKK and NF-kappaB activation. MyD88-dependent endocytosis of IL-1R1 following IL-1beta binding was required for the redox-dependent formation of an active endosomal receptor complex competent for IKK and NF-kappaB activation. Small interfering RNAs to either MyD88 or Rac1 inhibited IL-1beta induction of endosomal superoxide and NF-kappaB activation. However, MyD88 and Rac1 appear to be recruited independently to IL-1R1 following ligand stimulation. In this context, MyD88 binding was required for inducing endocytosis of IL-1R1 following ligand binding, while Rac1 facilitated the recruitment of Nox2 into the endosomal compartment and subsequent redox-dependent recruitment of TRAF6 to the MyD88/IL-1R1 complex. The identification of Nox-active endosomes helps explain how subcellular compartmentalization of redox signals can be used to direct receptor activation from the plasma membrane.
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, University of Iowa, 51 Newton Road, Iowa City, IA 52242, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.forename: Maged M
authors.initials: MM
authors.lastname: Harraz
authors.forename: Weihong
authors.initials: W
authors.lastname: Zhou
authors.forename: Liang N
authors.initials: LN
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.forename: Yulong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Tim
authors.initials: T
authors.lastname: Eggleston
authors.forename: Charles
authors.initials: C
authors.lastname: Yeaman
authors.forename: Botond
authors.initials: B
authors.lastname: Banfi
authors.forename: John F
authors.initials: JF
authors.lastname: Engelhardt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D053573:Receptors, Interleukin-1 Type I; D013481:Superoxides / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007375:Interleukin-1; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C107953:RAC1 protein, human; D034741:RNA, Small Interfering; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D048029:TNF Receptor-Associated Factor 6; D013481:Superoxides; D006861:Hydrogen Peroxide; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein