Spatiotemporal dynamics of innate immune signaling via RIG-I-like receptors

Proc Natl Acad Sci U S A. 2020 Jul 7;117(27):15778-15788. doi: 10.1073/pnas.1921861117. Epub 2020 Jun 22.


RIG-I, MDA5, and LGP2 comprise the RIG-I-like receptors (RLRs). RIG-I and MDA5 are essential pathogen recognition receptors sensing viral infections while LGP2 has been described as both RLR cofactor and negative regulator. After sensing and binding to viral RNA, including double-stranded RNA (dsRNA), RIG-I and MDA5 undergo cytosol-to-membrane relocalization to bind and signal through the MAVS adaptor protein on intracellular membranes, thus directing downstream activation of IRF3 and innate immunity. Here, we report examination of the dynamic subcellular localization of all three RLRs within the intracellular response to dsRNA and RNA virus infection. Observations from high resolution biochemical fractionation and electron microscopy, coupled with analysis of protein interactions and IRF3 activation, show that, in resting cells, microsome but not mitochondrial fractions harbor the central components to initiate innate immune signaling. LGP2 interacts with MAVS in microsomes, blocking the RIG-I/MAVS interaction. Remarkably, in response to dsRNA treatment or RNA virus infection, LGP2 is rapidly released from MAVS and redistributed to mitochondria, temporally correlating with IRF3 activation. We reveal that IRF3 activation does not take place on mitochondria but instead occurs at endoplasmic reticulum (ER)-derived membranes. Our observations suggest ER-derived membranes as key RLR signaling platforms controlled through inhibitory actions of LGP2 binding to MAVS wherein LGP2 translocation to mitochondria releases MAVS inhibition to facilitate RLR-mediated signaling of innate immunity.

Keywords: IRF3; LGP2; MAVS; RIG-I; innate immunity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • DEAD Box Protein 58 / genetics*
  • DEAD Box Protein 58 / immunology
  • Humans
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology
  • Interferon Regulatory Factor-3 / genetics
  • Interferon-Induced Helicase, IFIH1 / genetics*
  • Interferon-Induced Helicase, IFIH1 / immunology
  • Mitochondria / genetics
  • Mitochondria / immunology
  • RNA Helicases / genetics*
  • RNA Helicases / immunology
  • RNA, Double-Stranded / genetics
  • RNA, Viral / genetics
  • RNA, Viral / immunology
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Virus Diseases / genetics
  • Virus Diseases / immunology*
  • Virus Diseases / virology


  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • RNA, Double-Stranded
  • RNA, Viral
  • DHX58 protein, human
  • IFIH1 protein, human
  • DEAD Box Protein 58
  • Interferon-Induced Helicase, IFIH1
  • RNA Helicases