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.

T-cell Immunoglobulin and ITIM Domain (TIGIT) Receptor/Poliovirus Receptor (PVR) Ligand Engagement Suppresses Interferon-γ Production of Natural Killer Cells via β-Arrestin 2-mediated Negative Signaling

“…TRAF6 autoubiquitination initiates IB kinase activation (28,40). Recently, a large amount of negative regulators were reported to suppress autoubiquitination of TRAF6 that impairs NF-B signaling (23,44,45). Another recent study showed that the bacterial ITIM-containing protein Tir mediates recruitment of SHP1 to the adaptor TRAF6 and represses the autoubiquitination of TRAF6 (46).…”

“…To further validate these observations, we detected NF-B activation by using a luciferase reporter assay system. TRAF6 was used to activate the NF-B pathway in HEK293T cells as reported (23). Expectedly, ␤-arrestin 2 silencing dramatically increased NF-B activation (Fig.…”

c-Myb Enhances Breast Cancer Invasion and Metastasis through the Wnt/β-Catenin/Axin2 Pathway

“…Immunoprecipitation and Western blotting was performed as described previously (16). Actin or Tubulin protein levels were used as loading controls.…”

MicroRNA-351 inhibits denervation-induced muscle atrophy by targeting TRAF6

“…It is involved in activation of various signaling cascades including mitogen-activated protein kinase, nuclear factor-κB, and phosphoinositide 3-kinase/protein kinase B in response to various cytokines (6)(7)(8), and also important for the interaction with multiple components of the ubiquitin-proteasome system (UPS) in some cell types (9)(10)(11). Due to its biological traits, TRAF6 regulates skeletal muscle mass and UPS activation in denervation or starvation-induced muscle atrophy (6,12), and catalyzes lysine 63-linked polyubiquitination of several target proteins through its association with the dimeric ubiquitin-conjugating enzyme Ubc13/Uev1A (13).…”