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

ABSTRACT: Tight regulation of NF-?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 NF-?B activation. NLRX1 interacts with TRAF6 or I?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? and IKK? phosphorylation and NF-?B activation. Knockdown of NLRX1 in various cell types markedly enhances IKK phosphorylation and the production of NF-?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-?B activation by dynamically interacting with TRAF6 and the IKK complex.

SUBMITTER: Xia X 

PROVIDER: S-EPMC3150212 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature