NLRX1 is a regulator of mitochondrial antiviral immunity

Nature. 2008 Jan 31;451(7178):573-7. doi: 10.1038/nature06501. Epub 2008 Jan 16.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Line
  • Cloning, Molecular
  • Computational Biology
  • Humans
  • Interferon-beta / biosynthesis
  • Interferon-beta / genetics
  • Interferon-beta / metabolism
  • Mice
  • Mitochondria / immunology*
  • Mitochondria / metabolism*
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • NF-kappa B / metabolism
  • Protein Binding
  • Protein Transport
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Virus Replication
  • Viruses / immunology*


  • Adaptor Proteins, Signal Transducing
  • MAVS protein, human
  • Mitochondrial Proteins
  • NF-kappa B
  • NLRX1 protein, human
  • RNA, Small Interfering
  • Interferon-beta