Pathogen response: NLRX1 is a prospective, selective anti-infective
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The NLRX1 receptor inhibits the production of antiviral type I interferon β (IFN-β) by blocking the interaction between the RNA helicase RIG-I and the mitochondrial antiviral signaling protein MAVS.
Three classes of receptors — TLRs (Toll-like receptors), NLRs (nucleotide-binding domain, leucine-rich-repeat-containing proteins) and RLHs (RIG-like RNA helicases) — sense foreign biological material and mediate an IFN-β-based immune response. While TLRs detect extracellular material, NLRs and RLHs are tethered to the outer face of mitochondria and are thought to respond to cytoplasmic pathogens. For example, viral RNA binds to and activates RIG-I, which in turn stimulates MAVS to promote nuclear factor-κB (NF-κB)- or interferon regulatory factor 3 (IRF3)-mediated transcription of IFN-β. Some NLR family members can also detect pathogens; however, their biological function is not yet well understood. In Nature, Moore et al. now report that NLRX1 antagonizes the immune response to viral infection by inhibiting IFN-β production, likely by blocking the interaction between RIG-I and MAVS.
A bioinformatics screen for novel mitochondrial NLRs identified NLRX1, which localized to the outer mitochondrial membrane and directly interacted with MAVS in vivo. Expression of NLRX1, but not other NLRs, blocked MAVS-associated activation of NF-κB and expression of IFN-β in a dose-dependent manner. In addition, siRNA-mediated depletion of endogenous NLRX1 caused increased expression of IFN-β mRNA and NF-κB target genes, indicating that NLRX1 interferes with the MAVS-directed immune response.
Given that NLRX1 regulates IFN-β expression and NF-κB activity, the authors hypothesized that it could potentially modulate the response to viral infection. Indeed, depletion of NLRX1 during Sendai or Sindbis virus infection caused an eight-fold increase in IFN-β mRNA and protein levels compared to wild-type infected cells. Expression of the double-stranded RNA analogue poly(I:C) is known to trigger RLH-mediated activation of MAVS and induction of NF-κB and IFN-β. Exogenous NLRX1 significantly dampened the response to poly(I:C) in cultured cells, while siRNA against NLRX1 restored NF-κB and IFN-β levels.
How, then, does NLRX1 antagonize the antiviral response? Sendai virus infection enhances the association of MAVS and RIG-I, and NLRX1 expression blocked this interaction. As RIG-I and NLRX1 both bind to the caspase recruitment domain (CARD) domain of MAVS, the authors speculate that NLRX1 and RIG-I may compete for binding to MAVS — although with disparate effects; RIG-I binding heightened NF-κB and IFN-β expression, whereas NLRX1 binding repressed expression. NLRX1-mediated 'tuning' of the immune response could be important for regulating IFN-β signaling during viral infection, enabling precise control of the antiviral response. However, the mechanism by which NLRX1 is itself regulated awaits further study, due to the authors' observation that NLRX1 mRNA and protein levels remained stable upon activation of MAVS.
Emily J. Chenette Signaling Gateway
Reference
Moore, C. B. et al. NLRX1 is a regulator of mitochondrial antiviral immunity. Nature451, 573-577 (2008) | Article | PubMed |
