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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

Authors

  • Krieg A
  • Correa RG
  • Garrison JB
  • Le Negrate G
  • Welsh K
  • Huang Z
  • Knoefel WT
  • Reed JC

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

August 25, 2009

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI-56324
  • Agency: NCI NIH HHS, Id: P30 CA030199

Mesh Terms

  • 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