Peli1 facilitates TRIF-dependent Toll-like receptor signaling and proinflammatory cytokine production.
Toll-like receptors (TLRs) are pivotal in innate immunity and inflammation. Here we show that genetic deficiency in Peli1, an E3 ubiquitin ligase, attenuated the induction of proinflammatory cytokines by ligands of TLR3 and TLR4 and rendered mice resistant to septic shock. Peli1 was required for TLR3-induced activation of IkappaB kinase (IKK) and its 'downstream' target, transcription factor NF-kappaB, but was dispensable for IKK-NF-kappaB activation induced by several other TLRs and the interleukin 1 (IL-1) receptor. Notably, Peli1 bound to and ubiquitinated RIP1, a signaling molecule that mediates IKK activation induced by the TLR3 and TLR4 adaptor TRIF. Our findings suggest that Peli1 is a ubiquitin ligase needed for the transmission of TRIF-dependent TLR signals.
Chang
Mikyoung
M
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Jin
Wei
W
Sun
Shao-Cong
SC
D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D020690:GTPase-Activating Proteins / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D051550:I-kappa B Kinase / Q000276:immunology / Q000378:metabolism; D047468:Immunoprecipitation; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination
D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D020690:GTPase-Activating Proteins; D051550:I-kappa B Kinase; D016328:NF-kappa B; D009687:Nuclear Proteins; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; D044767:Ubiquitin-Protein Ligases; C490620:Ralbp1 protein, mouse; C476286:Ticam1 protein, mouse; C418046:Peli1 protein, mouse