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Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation.

Nature cell biology | Feb 3, 2009

http://www.ncbi.nlm.nih.gov/pubmed/19136968

Nuclear factor-kappaB (NF-kappaB) is a key transcription factor in inflammatory, anti-apoptotic and immune processes. The ubiquitin pathway is crucial in regulating the NF-kappaB 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-kappaB pathway by binding to NEMO (NF-kappaB essential modulator, also called IKKgamma) 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-kappaB signalling induced by pro-inflammatory cytokines such as TNF-alpha and IL-1beta 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-kappaB activation pathway through linear polyubiquitylation of NEMO.

Pubmed ID: 19136968 RIS Download

Mesh terms: Animals | Apoptosis | Carrier Proteins | Cell Line | Chimera | Cytokines | Intracellular Signaling Peptides and Proteins | Macromolecular Substances | Mice | Mice, Inbred C57BL | Mice, Inbred ICR | Mice, Knockout | Molecular Structure | NF-kappa B | Polymers | RING Finger Domains | Ubiquitin | Ubiquitin-Conjugating Enzymes | Ubiquitin-Protein Ligases | Ubiquitination

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