NLRX1 Protein Attenuates Inflammatory Responses to Infection by Interfering with the RIG-I-MAVS and TRAF6-NF-κB Signaling Pathways

• Published in: Immunity (Cambridge, Mass.) Vol. 34; no. 6; pp. 854 - 865
• Main Authors: Allen, Irving C., Moore, Chris B., Schneider, Monika, Lei, Yu, Davis, Beckley K., Scull, Margaret A., Gris, Denis, Roney, Kelly E., Zimmermann, Albert G., Bowzard, John B., Ranjan, Priya, Monroe, Kathryn M., Pickles, Raymond J., Sambhara, Suryaprakash, Ting, Jenny P.Y.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.06.2011
• Subjects: Adaptor Proteins, Signal Transducing - immunology; Adaptor Proteins, Signal Transducing - metabolism; Animals; Cells, Cultured; Influenza A Virus, H1N1 Subtype - immunology; Interferon-beta - biosynthesis; Interferon-beta - immunology; Interleukin-6 - biosynthesis; Interleukin-6 - immunology; Macrophages - immunology; Membrane Proteins - immunology; Membrane Proteins - metabolism; Mice; Mice, Knockout; Mitochondrial Proteins - deficiency; Mitochondrial Proteins - immunology; Nerve Tissue Proteins - immunology; Nerve Tissue Proteins - metabolism; NF-kappa B - immunology; NF-kappa B - metabolism; Orthomyxoviridae Infections - immunology; Signal Transduction; TNF Receptor-Associated Factor 6 - immunology; TNF Receptor-Associated Factor 6 - metabolism
• DOI: 10.1016/j.immuni.2011.03.026
• ISSN: 1074-7613

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. ► NLRX1 attenuates IFN induction by preventing the interaction between RIG-I and MAVS ► NLRX1 functions as a negative regulator of IFN-I and IL-6 during influenza infection ► NLRX1 attenuates inflammation by intersecting the TRAF6 pathway to affect NF-κB