RNF8 negatively regulates NF-kappaB signaling by targeting IkappaB kinase: implications for the regulation of inflammation signaling

Persistent or excess activation of NF-κB leads to cancer， autoimmune and inflammatory diseases. Therefore， activated NF-κB needs to be terminated after induction， which highlights the physiological significance of NF-κB-negative regulators. However， the molecular mechanisms that negatively regulate NF-κB are not well understood. Here， we report that Ring Finger Protein 8 (RNF8)， an E3 ubiquitin ligase， inhibits TNFα-mediated NF-κB activation by targeting IκB kinase (IKK). Upon TNFα stimulation， RNF8 binds to the catalytic subunits of IKK complex， resulting in inhibition of IKKα/β phosphorylation and subsequent NF-κB activation. RNF8 targets the IKK complex in a manner independent of its RING domain. We further provide evidence that the silencing of RNF8 results in enhanced TNFα-induced IKK activation， and an increase expression of NF-κB-induced inflammatory cytokine IL-8. Our study identifies a previously unrecognized role for RNF8 in the negative regulation of NF-κB activation by targeting and deactivating the IKK complex.