title: NLRX1 is a regulator of mitochondrial antiviral immunity.
abstract: The RIG-like helicase (RLH) family of intracellular receptors detect viral nucleic acid and signal through the mitochondrial antiviral signalling adaptor MAVS (also known as Cardif, VISA and IPS-1) during a viral infection. MAVS activation leads to the rapid production of antiviral cytokines, including type 1 interferons. Although MAVS is vital to antiviral immunity, its regulation from within the mitochondria remains unknown. Here we describe human NLRX1, a highly conserved nucleotide-binding domain (NBD)- and leucine-rich-repeat (LRR)-containing family member (known as NLR) that localizes to the mitochondrial outer membrane and interacts with MAVS. Expression of NLRX1 results in the potent inhibition of RLH- and MAVS-mediated interferon-beta promoter activity and in the disruption of virus-induced RLH-MAVS interactions. Depletion of NLRX1 with small interference RNA promotes virus-induced type I interferon production and decreases viral replication. This work identifies NLRX1 as a check against mitochondrial antiviral responses and represents an intersection of three ancient cellular processes: NLR signalling, intracellular virus detection and the use of mitochondria as a platform for anti-pathogen signalling. This represents a conceptual advance, in that NLRX1 is a modulator of pathogen-associated molecular pattern receptors rather than a receptor, and identifies a key therapeutic target for enhancing antiviral responses.
authors.affiliation: Department of Microbiology-Immunology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Chris B
authors.initials: CB
authors.lastname: Moore
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Bergstralh
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Duncan
authors.forename: Yu
authors.initials: Y
authors.lastname: Lei
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Morrison
authors.forename: Albert G
authors.initials: AG
authors.lastname: Zimmermann
authors.forename: Mary A
authors.initials: MA
authors.lastname: Accavitti-Loper
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Madden
authors.forename: Lijun
authors.initials: L
authors.lastname: Sun
authors.forename: Zhengmao
authors.initials: Z
authors.lastname: Ye
authors.forename: John D
authors.initials: JD
authors.lastname: Lich
authors.forename: Mark T
authors.initials: MT
authors.lastname: Heise
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Chen
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D019295:Computational Biology; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000276:immunology* / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014779:Virus Replication; D014780:Viruses / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C505371:MAVS protein, human; D024101:Mitochondrial Proteins; D016328:NF-kappa B; C527006:NLRX1 protein, human; D034741:RNA, Small Interfering; D016899:Interferon-beta