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- Title
NLRX1 is a regulator of mitochondrial antiviral immunity.
- Authors
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; Ting, Jenny P-Y.
- 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.
- Subjects
DNA helicases; MITOCHONDRIAL DNA; ANTIVIRAL agents; LEUCINE; PATHOGENIC microorganisms; VIRAL replication; CYTOKINES; INTERFERONS; INTRACELLULAR pathogens
- Publication
Nature, 2008, Vol 451, Issue 7178, p573
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature06501