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NLRX1 protein attenuates inflammatory responses to infection by interfering with the RIG-I-MAVS and TRAF6-NF-κB signaling pathways.

Immunity | Jun 24, 2011

The nucleotide-binding domain and leucine-rich-repeat-containing (NLR) proteins regulate innate immunity. Although the positive regulatory impact of NLRs is clear, their inhibitory roles are not well defined. We showed that Nlrx1(-/-) mice exhibited increased expression of antiviral signaling molecules IFN-β, STAT2, OAS1, and IL-6 after influenza virus infection. Consistent with increased inflammation, Nlrx1(-/-) mice exhibited marked morbidity and histopathology. Infection of these mice with an influenza strain that carries a mutated NS-1 protein, which normally prevents IFN induction by interaction with RNA and the intracellular RNA sensor RIG-I, further exacerbated IL-6 and type I IFN signaling. NLRX1 also weakened cytokine responses to the 2009 H1N1 pandemic influenza virus in human cells. Mechanistically, Nlrx1 deletion led to constitutive interaction of MAVS and RIG-I. Additionally, an inhibitory function is identified for NLRX1 during LPS activation of macrophages where the MAVS-RIG-I pathway was not involved. NLRX1 interacts with TRAF6 and inhibits NF-κB activation. Thus, NLRX1 functions as a checkpoint of overzealous inflammation.

Pubmed ID: 21703540 RIS Download

Mesh terms: Adaptor Proteins, Signal Transducing | Animals | Cells, Cultured | Influenza A Virus, H1N1 Subtype | Interferon-beta | Interleukin-6 | Macrophages | Membrane Proteins | Mice | Mice, Knockout | Mitochondrial Proteins | NF-kappa B | Nerve Tissue Proteins | Orthomyxoviridae Infections | Signal Transduction | TNF Receptor-Associated Factor 6

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Associated grants

  • Agency: NIAID NIH HHS, Id: F32 AI082895
  • Agency: NIAID NIH HHS, Id: F32 AI082895-01
  • Agency: NIAID NIH HHS, Id: F32-AI-082895-01
  • Agency: NCI NIH HHS, Id: R01 CA156330
  • Agency: NIAMS NIH HHS, Id: T32-AR007416
  • Agency: NCI NIH HHS, Id: T32-CA009156
  • Agency: NIAID NIH HHS, Id: U19 AI067798
  • Agency: NIAID NIH HHS, Id: U19-AI067798
  • Agency: NIAID NIH HHS, Id: U19-AI077437
  • Agency: NIAID NIH HHS, Id: U54-AI057157

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