Mitofusin 2 inhibits mitochondrial antiviral signaling

Sci Signal. 2009 Aug 18;2(84):ra47. doi: 10.1126/scisignal.2000287.

Abstract

The innate immune response to viral infection involves the activation of multiple signaling steps that culminate in the production of type I interferons (IFNs). Mitochondrial antiviral signaling (MAVS), a mitochondrial outer membrane adaptor protein, plays an important role in this process. Here, we report that mitofusin 2 (Mfn2), a mediator of mitochondrial fusion, interacts with MAVS to modulate antiviral immunity. Overexpression of Mfn2 resulted in the inhibition of retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA-5), two cytosolic sensors of viral RNA, as well as of MAVS-mediated activation of the transcription factors interferon regulatory factor 3 (IRF-3) and nuclear factor kappaB (NF-kappaB). In contrast, loss of endogenous Mfn2 enhanced virus-induced production of IFN-beta and thereby decreased viral replication. Structure-function analysis revealed that Mfn2 interacted with the carboxyl-terminal region of MAVS through a heptad repeat region, providing a structural perspective on the regulation of the mitochondrial antiviral response. Our results suggest that Mfn2 acts as an inhibitor of antiviral signaling, a function that may be distinct from its role in mitochondrial dynamics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Blotting, Western
  • Cell Line
  • Cells, Cultured
  • Chromatography, Gel
  • Fibroblasts / cytology
  • Fibroblasts / metabolism*
  • GTP Phosphohydrolases
  • HeLa Cells
  • Host-Pathogen Interactions
  • Humans
  • Immunoprecipitation
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism
  • Measles virus / physiology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism*
  • Mitochondria / virology
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Models, Biological
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Protein Binding
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA Interference
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism
  • Transfection

Substances

  • Adaptor Proteins, Signal Transducing
  • Interferon Regulatory Factor-3
  • MAVS protein, human
  • Membrane Proteins
  • Mitochondrial Proteins
  • NF-kappa B
  • TNF Receptor-Associated Factor 6
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human
  • GTP Phosphohydrolases
  • MFN2 protein, human