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.
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
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
Immunity
Date: Jun. 24, 2011
PubMed ID: 21703539
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