Journal Article

XIAP mediates NOD signaling via interaction with RIP2

Reed, John C, Welsh, Kate, Le Negrate, Gaëlle, Krieg, Andreas, Correa, Ricardo G, Garrison, Jason B, Huang, Ziwei, Knoefel, Wolfram T

2009

Overview

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-κB 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-κB 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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: antagonists / Antibodies / Apoptosis / Bacteria / Biological Sciences / Cell Line / Cell Line, Tumor / Cell lines / Enzyme-Linked Immunosorbent Assay / Gene Expression / Green Fluorescent Proteins - genetics / Green Fluorescent Proteins - metabolism / HCT116 Cells / HEK293 cells / Humans / Immune system / Immunoblotting / Immunoprecipitation / innate immunity / Interleukin-8 - metabolism / intracellular signaling peptides and proteins / Kinases / Ligands / Luciferases - genetics / Luciferases - metabolism / Mutation / NF-kappa B - genetics / NF-kappa B - metabolism / Nod1 Signaling Adaptor Protein - genetics / Nod1 Signaling Adaptor Protein - metabolism / Nod2 Signaling Adaptor Protein - genetics / Nod2 Signaling Adaptor Protein - metabolism / pathogens / Peptides / peptidoglycans / Plasmids / Protein Binding / Proteins / Receptor-Interacting Protein Serine-Threonine Kinase 2 - genetics / Receptor-Interacting Protein Serine-Threonine Kinase 2 - metabolism / Recombinant Fusion Proteins - genetics / Recombinant Fusion Proteins - metabolism / Reporter genes / Reverse Transcriptase Polymerase Chain Reaction / RNA, Small Interfering - genetics / Signal Transduction / transcription factor NF-kappa B / Transfection / X-Linked Inhibitor of Apoptosis Protein - genetics / X-Linked Inhibitor of Apoptosis Protein - metabolism