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NLRX1 negatively regulates TLR-induced NF-κB signaling by targeting TRAF6 and IKK.

Tight regulation of NF-κB signaling is essential for innate and adaptive immune responses, yet the molecular mechanisms responsible for its negative regulation are not completely understood. Here, we report that NLRX1, a NOD-like receptor family member, negatively regulates Toll-like receptor-mediated NF-κB activation. NLRX1 interacts with TRAF6 or IκB kinase (IKK) in an activation signal-dependent fashion. Upon LPS stimulation, NLRX1 is rapidly ubiquitinated, disassociates from TRAF6, and then binds to the IKK complex, resulting in inhibition of IKKα and IKKβ phosphorylation and NF-κB activation. Knockdown of NLRX1 in various cell types markedly enhances IKK phosphorylation and the production of NF-κB-responsive cytokines after LPS stimulation. We further provide in vivo evidence that NLRX1 knockdown in mice markedly enhances susceptibility to LPS-induced septic shock and plasma IL-6 level. Our study identifies a previously unrecognized role for NLRX1 in the negative regulation of TLR-induced NF-κB activation by dynamically interacting with TRAF6 and the IKK complex.

Pubmed ID: 21703539

Authors

  • Xia X
  • Cui J
  • Wang HY
  • Zhu L
  • Matsueda S
  • Wang Q
  • Yang X
  • Hong J
  • Songyang Z
  • Chen ZJ
  • Wang RF

Journal

Immunity

Publication Data

June 24, 2011

Associated Grants

  • Agency: NCI NIH HHS, Id: P01 CA094237
  • Agency: NCI NIH HHS, Id: P01 CA094237-10
  • Agency: NCI NIH HHS, Id: P50 CA126752
  • Agency: NCI NIH HHS, Id: P50 CA126752-05
  • Agency: NCI NIH HHS, Id: R01 CA090327
  • Agency: NCI NIH HHS, Id: R01 CA090327-09
  • Agency: NCI NIH HHS, Id: R01 CA101795
  • Agency: NCI NIH HHS, Id: R01 CA101795-05
  • Agency: NCI NIH HHS, Id: R01 CA116408
  • Agency: NCI NIH HHS, Id: R01 CA116408-05
  • Agency: NCI NIH HHS, Id: R01 CA121191
  • Agency: NCI NIH HHS, Id: R01 CA121191-05

Mesh Terms

  • Animals
  • Cell Line
  • Cytokines
  • Humans
  • I-kappa B Kinase
  • Lipopolysaccharides
  • Mice
  • Mitochondrial Proteins
  • NF-kappa B
  • Phosphorylation
  • Protein Binding
  • Signal Transduction
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptors
  • Ubiquitination