NLRX1 is a regulator of mitochondrial antiviral immunity

Chris B. Moore, Daniel T. Bergstralh, Joseph A. Duncan, Yu Lei, Thomas E. Morrison, Albert G. Zimmermann, Mary A. Accavitti-Loper, Victoria J. Madden, Lijun Sun, Zhengmao Ye, John D. Lich, Mark T. Heise, Zhijian Chen, Jenny P Y Ting

Research output: Contribution to journalArticle

378 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)573-577
Number of pages5
JournalNature
Volume451
Issue number7178
DOIs
StatePublished - Jan 31 2008

ASJC Scopus subject areas

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    Moore, C. B., Bergstralh, D. T., Duncan, J. A., Lei, Y., Morrison, T. E., Zimmermann, A. G., Accavitti-Loper, M. A., Madden, V. J., Sun, L., Ye, Z., Lich, J. D., Heise, M. T., Chen, Z., & Ting, J. P. Y. (2008). NLRX1 is a regulator of mitochondrial antiviral immunity. Nature, 451(7178), 573-577. https://doi.org/10.1038/nature06501