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

Biochemical and Biophysical Research Communications
Shijuan GaoRuixue Xu

Abstract

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.

Citations

Aug 22, 2020·Journal of Clinical Laboratory Analysis·Guang-Zhang LiZhi-Xin Liu
Feb 2, 2020·European Heart Journal·Luca LiberaleGiovanni G Camici
Aug 28, 2020·Mediators of Inflammation·Liguo ZhuShenghong Zhang
Jul 17, 2021·The Biochemical Journal·Jack A PrescottSimon J Cook

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