NLRX1 Negatively Regulates TLR-Induced NF-κB Signaling by Targeting TRAF6 and IKK

Tight regulation of NF-kappa B 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 NE-kappa B activation. NLRX1 interacts with TRAF6 or I kappa B 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 IKK alpha and IKK(3 phosphorylation and NF-kappa B activation. Knockdown of NLRX1 in various cell types markedly enhances IKK phosphorylation and the production of NF-kappa B-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-kappa B activation by dynamically interacting with TRAF6 and the IKK complex.