IWAI Kazuhiro ≪Biophysics and Biochemistry≫ “Involvement of linear polyubiquitylation of NEMO in NF-κB activation”
Publish Nature Cell Biology 11,123-132, 2009
Nuclear factor-κB (NF-κB) is a key transcription factor in inflammatory, anti-apoptotic and immune processes. The ubiquitin pathwayis crucial in regulating the NF-κB pathway. We have found that the LUBAC ligase complex, composed of the two RING finger proteins, HOIL-1L and HOIP, conjugates a head-to-tail-linked linear polyubiquitin chain to substrates. Here, we demonstrate that LUBAC activates the canonical NF-κB pathway by binding to NEMO (NF-κB essential modulator, also called IKKγ) and conjugates linear polyubiquitin chains onto specific Lys residues in the CC2-LZ domain of NEMO in a Ubc13-independent manner. Moreover, in HOIL-1 knockout mice and cells derived from these mice, NF-κB signalling induced by pro-inflammatory cytokines such as TNF-α and IL-1β was suppressed, resulting in enhanced TNF-α-induced apoptosis in hepatocytes of HOIL-1 knockout mice. These results indicate that LUBAC is involved in the physiological regulation of the canonical NF-κB activation pathway through linear polyubiquitylation of NEMO.