title: Rip1 mediates the Trif-dependent toll-like receptor 3- and 4-induced NF-{kappa}B activation but does not contribute to interferon regulatory factor 3 activation.
abstract: Rip1 is required for IkappaB kinase activation in response to tumor necrosis factor alpha (TNF-alpha) and has been implicated in the Toll-like receptor 3 (TLR3) response to double-stranded RNA. Cytokine production is impaired when rip1-/- cells are treated with TNF-alpha, poly(I-C), or lipopolysaccharide, implicating Rip1 in the Trif-dependent TLR3 and TLR4 pathways. To examine the role of Rip1 in the Trif-dependent TLR4 pathway, we generated rip1-/- MyD88-/- cells. Lipopolysaccharide failed to stimulate NF-kappaB activation in rip1-/-MyD88-/- cells, revealing that Rip1 is also required for the Trif-dependent TLR4-induced NF-kappaB pathway. In addition to activating NF-kappaB, TLR3/4 pathways also stimulate interferon regulatory factor 3 activation. However, we find that Rip1 expression stimulates NF-kappaB but not interferon regulatory factor 3 activity. In the TNF-alpha pathway, Rip1 interacts with the E3 ubiquitin ligase Traf2 and is modified by polyubiquitin chains. Upon TLR3 activation, Rip1 is also modified by polyubiquitin chains and is recruited to TLR3 along with Traf6 and the ubiquitin-activated kinase Tak1. These studies suggest that Rip1 uses a similar, ubiquitin-dependent mechanism to activate IkappaB kinase-beta in response to TNF-alpha and TLR3 ligands.
authors.affiliation: Departments of Cancer Biology and Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Cusson-Hermance
authors.forename: Smriti
authors.initials: S
authors.lastname: Khurana
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Lee
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Kelliher
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D002478:Cells, Cultured; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D047468:Immunoprecipitation; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000943:Antigens, Differentiation; D020690:GTPase-Activating Proteins; D020672:I-kappa B Proteins; D050838:Interferon Regulatory Factor-3; D008024:Ligands; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011971:Receptors, Immunologic; D047992:TNF Receptor-Associated Factor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D025801:Ubiquitin; D000099151:MAP Kinase Kinase Kinase 7; C083487:I kappa B beta protein; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; C490620:Ralbp1 protein, mouse; C476286:Ticam1 protein, mouse