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

SummaryTight 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (158 K)Download as PowerPoint slideHighlights► NLRX1 negatively regulates Toll-like receptor-mediated NF-κB activation ► NLRX1 disassociates from TRAF6 and then binds to the IKK complex after stimulation ► NLRX1 knockdown enhances NF-κB activation and cytokine production after stimulation ► NLRX1 knockdown in mice enhances susceptibility to septic shock and plasma IL-6