Involvement of linear polyubiquitylation of NEMO in NF-κB activation

Nuclear factor-kappa B (NF-kappa B) is a key transcription factor in inflammatory, anti-apoptotic and immune processes. The ubiquitin pathway is crucial in regulating the NF-kappa B 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-kappa B pathway by binding to NEMO (NF-kappa B essential modulator, also called IKK gamma) 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-kappa B signalling induced by pro-inflammatory cytokines such as TNF-alpha and IL-1 beta was suppressed, resulting in enhanced TNF-alpha-induced apoptosis in hepatocytes of HOIL-1 knockout mice. These results indicate that LUBAC is involved in the physiological regulation of the canonical NF-kappa B activation pathway through linear polyubiquitylation of NEMO.