Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line
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Chimera
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Cytokines / metabolism
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Cytokines / pharmacology
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Macromolecular Substances / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Inbred ICR
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Mice, Knockout
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Molecular Structure
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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Polymers / metabolism
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RING Finger Domains / genetics
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Ubiquitin / genetics
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Ubiquitin / metabolism*
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Ubiquitin-Conjugating Enzymes / genetics
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Ubiquitin-Conjugating Enzymes / metabolism
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitination* / genetics
Substances
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Carrier Proteins
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Cytokines
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HOIL-1L protein, mouse
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Intracellular Signaling Peptides and Proteins
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Macromolecular Substances
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NEMO protein, mouse
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NF-kappa B
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Polymers
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Ubiquitin
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Ube2n protein, mouse
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Ubiquitin-Conjugating Enzymes
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Rnf31 protein, mouse
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Ubiquitin-Protein Ligases