XIAP mediates NOD signaling via interaction with RIP2.
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.
Pubmed ID: 19667203 RIS Download
Cell Line | Cell Line, Tumor | Enzyme-Linked Immunosorbent Assay | Gene Expression | Green Fluorescent Proteins | HCT116 Cells | Humans | Immunoblotting | Immunoprecipitation | Interleukin-8 | Luciferases | Mutation | NF-kappa B | Nod1 Signaling Adaptor Protein | Nod2 Signaling Adaptor Protein | Protein Binding | RNA, Small Interfering | Receptor-Interacting Protein Serine-Threonine Kinase 2 | Recombinant Fusion Proteins | Reverse Transcriptase Polymerase Chain Reaction | Signal Transduction | Transfection | X-Linked Inhibitor of Apoptosis Protein