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

Immunity | Jun 24, 2011

http://www.ncbi.nlm.nih.gov/pubmed/21703539

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 RIS Download

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

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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

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