title: UBE2O negatively regulates TRAF6-mediated NF-κB activation by inhibiting TRAF6 polyubiquitination.
abstract: Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) is a key regulator of the activation of transcription factor NF-κB by the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) superfamily. Recruitment of TRAF6 to the receptor-associated IRAK1-IRAK4-MyD88 adaptor protein complex induces lysine 63 (K63) autopolyubiquitination of TRAF6, which leads to further recruitment of downstream regulators, such as TAB2/3 and TAK1, and subsequently triggers NF-κB activation. Here, we identified the putative E2 ubiquitin-conjugating (UBC) enzyme UBE2O as a novel negative regulator of TRAF6-dependent NF-κB signaling. We found that UBE2O binds to TRAF6 to inhibit its K63-polyubiquitination, and to prevent the activation of NF-κB by IL-1β and lipopolysaccharides (LPS). We further show that the inhibitory effect of UBE2O is independent of its carboxy-terminal UBC domain. In contrast, we found that UBE2O acts to disrupt the IL-1β-induced association of TRAF6 with MyD88. These results provide novel insight into the regulation of signaling by IL-1R/TLR and TRAF6.
authors: Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands and Centre for Biomedical Genetics, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands.
authors: Xiaofei
authors: X
authors: Zhang
authors: Juan
authors: J
authors: Zhang
authors: Long
authors: L
authors: Zhang
authors: Hans
authors: H
authors: van Dam
authors: Peter
authors: P
authors: ten Dijke
mesh_terms: D002460:Cell Line; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics / Q000502:physiology*
chemical_list: C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D044763:Ubiquitin-Conjugating Enzymes
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