Abstract
Despite their homology, IκB kinase α (IKKα) and IKKβ have divergent roles in NF-κB signaling. IKKβ strongly activates NF-κB while IKKα can downregulate NF-κB under certain circumstances. Given this, identifying independent substrates for these kinases could help delineate their divergent roles. Peptide substrate array technology followed by bioinformatic screening identified TRAF4 as a substrate for IKKα. Like IKKα, TRAF4 is atypical within its family because it is the only TRAF family member to negatively regulate innate immune signaling. IKKα's phosphorylation of serine-426 on TRAF4 was required for this negative regulation. Binding to the Crohn's disease susceptibility protein, NOD2, is required for TRAF4 phosphorylation and subsequent inhibition of NOD2 signaling. Structurally, serine-426 resides within an exaggerated β-bulge in TRAF4 that is not present in the other TRAF proteins, and phosphorylation of this site provides a structural basis for the atypical function of TRAF4 and its atypical role in NOD2 signaling.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Base Sequence
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Binding Sites
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Cell Line
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Crohn Disease / genetics
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Crohn Disease / immunology
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Crohn Disease / metabolism
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DNA Primers / genetics
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Down-Regulation
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HCT116 Cells
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HEK293 Cells
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Humans
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I-kappa B Kinase / genetics
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I-kappa B Kinase / immunology
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I-kappa B Kinase / metabolism*
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Immunity, Innate*
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Mice
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Models, Molecular
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Molecular Sequence Data
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NF-kappa B / metabolism
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Nod2 Signaling Adaptor Protein / genetics
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Nod2 Signaling Adaptor Protein / metabolism
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Peptide Library
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Phosphorylation
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Protein Stability
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Protein Structure, Tertiary
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / immunology
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Recombinant Fusion Proteins / metabolism
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Sequence Homology, Amino Acid
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Serine / chemistry
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Signal Transduction / immunology
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Substrate Specificity
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TNF Receptor-Associated Factor 4 / chemistry
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TNF Receptor-Associated Factor 4 / immunology
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TNF Receptor-Associated Factor 4 / metabolism*
Substances
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DNA Primers
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NF-kappa B
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NOD2 protein, human
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Nod2 Signaling Adaptor Protein
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Nod2 protein, mouse
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Peptide Library
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Recombinant Fusion Proteins
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TNF Receptor-Associated Factor 4
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TRAF4 protein, human
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Traf4 protein, mouse
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Serine
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Chuk protein, mouse
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I-kappa B Kinase