Abstract
NOD1 and NOD2 are members of the NOD-like receptor (NLR) protein family that are involved in sensing the presence of pathogens and are a component of the innate immune system. Upon activation by specific bacterial peptides derived from peptidoglycans, NODs interact via a CARD-CARD interaction with the receptor-interacting protein kinase RIP2, an inducer of NF-kappaB activation. In this report, we show that NOD signaling is dependent on XIAP, a member of the inhibitor of apoptosis protein (IAP) family. Cells deficient in XIAP exhibit a marked reduction in NF-kappaB activation induced by microbial NOD ligands and by over-expression of NOD1 or NOD2. Moreover, we show that XIAP interacts with RIP2 via its BIR2 domain, which could be disrupted by XIAP antagonists SMAC and SMAC-mimicking compounds. Both NOD1 and NOD2 associated with XIAP in a RIP2-dependent manner, providing evidence that XIAP associates with the NOD signalosome. Taken together, our data suggest a role for XIAP in regulating innate immune responses by interacting with NOD1 and NOD2 through interaction with RIP2.
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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Cell Line
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Cell Line, Tumor
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Enzyme-Linked Immunosorbent Assay
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Gene Expression
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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HCT116 Cells
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Humans
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Immunoblotting
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Immunoprecipitation
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Interleukin-8 / metabolism
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Luciferases / genetics
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Luciferases / metabolism
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Mutation
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Nod1 Signaling Adaptor Protein / genetics
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Nod1 Signaling Adaptor Protein / metabolism*
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Nod2 Signaling Adaptor Protein / genetics
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Nod2 Signaling Adaptor Protein / metabolism*
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Protein Binding
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RNA, Small Interfering / genetics
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Receptor-Interacting Protein Serine-Threonine Kinase 2 / genetics
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Receptor-Interacting Protein Serine-Threonine Kinase 2 / metabolism*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction*
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Transfection
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X-Linked Inhibitor of Apoptosis Protein / genetics
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X-Linked Inhibitor of Apoptosis Protein / metabolism*
Substances
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Interleukin-8
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NF-kappa B
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NOD1 protein, human
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NOD2 protein, human
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Nod1 Signaling Adaptor Protein
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Nod2 Signaling Adaptor Protein
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RNA, Small Interfering
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Recombinant Fusion Proteins
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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Green Fluorescent Proteins
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Luciferases
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RIPK2 protein, human
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Receptor-Interacting Protein Serine-Threonine Kinase 2