title: NLRX1 negatively regulates TLR-induced NF-κB signaling by targeting TRAF6 and IKK.
abstract: 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.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Xia
authors.forename: Jun
authors.initials: J
authors.lastname: Cui
authors.forename: Helen Y
authors.initials: HY
authors.lastname: Wang
authors.forename: Liang
authors.initials: L
authors.lastname: Zhu
authors.forename: Satoko
authors.initials: S
authors.lastname: Matsueda
authors.forename: Qinfu
authors.initials: Q
authors.lastname: Wang
authors.forename: Xiaoang
authors.initials: X
authors.lastname: Yang
authors.forename: Jun
authors.initials: J
authors.lastname: Hong
authors.forename: Zhou
authors.initials: Z
authors.lastname: Songyang
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
authors.forename: Rong-Fu
authors.initials: RF
authors.lastname: Wang
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000276:immunology; D006801:Humans; D051550:I-kappa B Kinase / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D024101:Mitochondrial Proteins / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000276:immunology* / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology*; D054875:Ubiquitination
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D024101:Mitochondrial Proteins; D016328:NF-kappa B; C555655:NLRX1 protein, mouse; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D051550:I-kappa B Kinase