Graduate School of Frontier Biosciences, Osaka University


Involvement of linear polyubiquitylation of NEMO in NF-κB activation

Journal Nat Cell Biol 11, 123-132 (2009)
Authors Tokunaga F, Sakata S, Saeki Y, Satomi Y, Kirisako T, Kamei K, Nakagawa T, Kato M, Murata S, Yamaoka S, Yamamoto M, Akira S, Takao T, Tanaka K, Iwai K.
Title Involvement of linear polyubiquitylation of NEMO in NF-κB activation
PubMed 19136968
Abstract 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.