title: NLRX1 protein attenuates inflammatory responses to infection by interfering with the RIG-I-MAVS and TRAF6-NF-κB signaling pathways.
abstract: The nucleotide-binding domain and leucine-rich-repeat-containing (NLR) proteins regulate innate immunity. Although the positive regulatory impact of NLRs is clear, their inhibitory roles are not well defined. We showed that Nlrx1(-/-) mice exhibited increased expression of antiviral signaling molecules IFN-β, STAT2, OAS1, and IL-6 after influenza virus infection. Consistent with increased inflammation, Nlrx1(-/-) mice exhibited marked morbidity and histopathology. Infection of these mice with an influenza strain that carries a mutated NS-1 protein, which normally prevents IFN induction by interaction with RNA and the intracellular RNA sensor RIG-I, further exacerbated IL-6 and type I IFN signaling. NLRX1 also weakened cytokine responses to the 2009 H1N1 pandemic influenza virus in human cells. Mechanistically, Nlrx1 deletion led to constitutive interaction of MAVS and RIG-I. Additionally, an inhibitory function is identified for NLRX1 during LPS activation of macrophages where the MAVS-RIG-I pathway was not involved. NLRX1 interacts with TRAF6 and inhibits NF-κB activation. Thus, NLRX1 functions as a checkpoint of overzealous inflammation.
authors.affiliation: The Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Irving C
authors.initials: IC
authors.lastname: Allen
authors.forename: Chris B
authors.initials: CB
authors.lastname: Moore
authors.forename: Monika
authors.initials: M
authors.lastname: Schneider
authors.forename: Yu
authors.initials: Y
authors.lastname: Lei
authors.forename: Beckley K
authors.initials: BK
authors.lastname: Davis
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Scull
authors.forename: Denis
authors.initials: D
authors.lastname: Gris
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Roney
authors.forename: Albert G
authors.initials: AG
authors.lastname: Zimmermann
authors.forename: John B
authors.initials: JB
authors.lastname: Bowzard
authors.forename: Priya
authors.initials: P
authors.lastname: Ranjan
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Monroe
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Pickles
authors.forename: Suryaprakash
authors.initials: S
authors.lastname: Sambhara
authors.forename: Jenny P Y
authors.initials: JP
authors.lastname: Ting
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D016899:Interferon-beta / Q000096:biosynthesis / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000276:immunology / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D011956:Receptors, Cell Surface; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000276:immunology / Q000378:metabolism; D000097905:Roundabout Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016899:Interferon-beta; D015850:Interleukin-6; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D048029:TNF Receptor-Associated Factor 6; C512612:MAVS protein, mouse; C555655:NLRX1 protein, mouse; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins