NF-κB-mediated degradation of the co-activator RIP140 regulates inflammatory response and contributes to endotoxin tolerance

Endotoxin tolerance (ET) triggered by prior exposure to Toll-like receptor (TLR) ligands provides a mechanism to dampen inflammatory cytokines. Receptor-interacting protein 140 (RIP140) interacts with NF-κB to regulate the expression of proinflammatory cytokine genes. We identify lipopolysaccharide (LPS) stimulation of Syk-mediated tyrosine phosphorylation on RIP140 and RelA interaction with RIP140. These events increase recruitment of SOCS1-Rbx1 (SCF) E3 ligase to tyrosine-phosphorylated RIP140, thereby degrading RIP140 to inactivate inflammatory cytokine genes. Macrophages expressing a non-degradable RIP140 were resistant to the establishment of ET for specific genes. The results reveal RelA as an adaptor for SCF ubiquitin ligase to fine-tune NF-κB target genes by targeting co-activator RIP140, and an unexpected role for RIP140 protein degradation in resolving inflammation and ET.