Figure 7
From: Cereblon negatively regulates TLR4 signaling through the attenuation of ubiquitination of TRAF6
Crbn−/− mice exhibit a higher mortality rate following LPS challenge. (a) Crbn−/− (n=8) and Crbn+/+ (n=8) mice were injected intraperitoneally with 7.5 mg/kg LPS in 100 μl of PBS. Survival was monitored for 7 days after LPS challenge. (b,c) Serum from mice taken at different times after LPS challenge was isolated, and the concentrations of the TNF-α (b) and IL-6 (c) cytokines were measured with a BD Cytometric Bead Array. Error bars represent the mean±S.D. of eight samples. *P<0.05 (d) A schematic model of the negative regulation of CRBN in TLR4 signaling. Upon TLR4 stimulation, ubiquitinated TRAF6 is associated with the TAB2–TAK–TAB1 complex though the interaction between its poly-ubiquitinated chain and TAB2, TAB2 is ubiquitinated, and the complex facilities the activation of TAK1. Simultaneously, the IKK complex is associated with the former complex through the poly-ubiquitinated chain and TAB2, leading to the activation of IKKs (left). In contrast, the interaction between CRBN and TRAF6 may lead to the attenuation of ubiquitination of TRAF6 by masking the K124 residue of TRAF6 and inhibiting the association of the TAK1–TAB1–TAB2 complex to TRAF6, leading to inhibition of ubiquitination of TAB2 and decreased association of the IKK complex with ubiquitinated TAB2 (right)
