GSBS Student Publications


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

UMMS Affiliation

Department of Cancer Biology; Department of Medicine, Division of Infectious Diseases and Immunology



Document Type


Medical Subject Headings

Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Animals; Antigens, Differentiation; Blotting, Western; Cells, Cultured; GTPase-Activating Proteins; Humans; I-kappa B Proteins; Immunoprecipitation; Interferon Regulatory Factor-3; Kidney; Ligands; Lipopolysaccharides; MAP Kinase Kinase Kinases; Mice; Mice, Knockout; Myeloid Differentiation Factor 88; NF-kappa B; Receptors, Immunologic; TNF Receptor-Associated Factor 2; Toll-Like Receptor 3; Toll-Like Receptor 4; Transfection; Ubiquitin


Cancer Biology | Immunology and Infectious Disease | Life Sciences | Medicine and Health Sciences


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.

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Citation: J Biol Chem. 2005 Nov 4;280(44):36560-6. Epub 2005 Aug 22. Link to article on publisher's site

DOI of Published Version


Related Resources

Link to article in PubMed

Journal Title

The Journal of biological chemistry

PubMed ID