1. NLRX1 is a regulator of mitochondrial antiviral immunity.
- Author
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Moore, Chris B., Bergstralh, Daniel T., Duncan, Joseph A., Yu Lei, Morrison, Thomas E., Zimmermann, Albert G., Accavitti-Loper, Mary A., Madden, Victoria J., Lijun Sun, Zhengmao Ye, Lich, John D., Heise, Mark T., Zhijian Chen, and Ting, Jenny P-Y.
- Subjects
DNA helicases ,MITOCHONDRIAL DNA ,ANTIVIRAL agents ,LEUCINE ,PATHOGENIC microorganisms ,VIRAL replication ,CYTOKINES ,INTERFERONS ,INTRACELLULAR pathogens - 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-β 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. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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