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MAVS polymers smaller than 80 nm induce mitochondrial membrane remodeling and interferon signaling

Ming-Shih Hwang1, Jérôme Boulanger2, Jonathan D Howe2

  • 1Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, UK.

The FEBS Journal
|February 5, 2019
PubMed

Insights

Double-stranded RNA (dsRNA) sensing by RIG-I-like receptors (RLRs) triggers mitochondrial antiviral-signaling protein (MAVS) activation. MAVS membrane tethering restrains polymerization, enabling mitochondrial remodeling and apoptosis during viral infection.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Double-stranded RNA (dsRNA) is a key viral signature recognized by RIG-I-like receptors (RLRs).
  • RLR activation leads to the assembly of mitochondrial antiviral-signaling protein (MAVS) into signaling complexes.
  • The current model proposes MAVS forms prion-like helical fibrils, but in-cell evidence is lacking.

Purpose of the Study:

  • To investigate the in-cell structure and dynamics of MAVS signaling complexes upon dsRNA sensing.
  • To determine the role of the MAVS transmembrane domain in its activation and downstream signaling.
  • To clarify the mechanism of MAVS-mediated antiviral response and apoptosis.

Main Methods:

  • Super-resolution light microscopy to visualize MAVS complexes in cells.
  • Quantitative image analysis to determine the size of MAVS signaling complexes and fibrils.
  • Analysis of MAVS mutants lacking the transmembrane domain to assess its function.

Main Results:

  • MAVS activation by dsRNA induces significant mitochondrial membrane remodeling.
  • MAVS signaling complexes and associated fibrils are smaller than 80 nm in cellular contexts.
  • The MAVS transmembrane domain is essential for dsRNA-induced mitochondrial remodeling, interferon signaling, and apoptosis.

Conclusions:

  • MAVS does not form large, self-propagating fibrils as previously modeled.
  • Membrane tethering of MAVS by its transmembrane domain restricts its polymerization.
  • This membrane-anchoring mechanism is crucial for effective mitochondrial remodeling and apoptosis in response to dsRNA.
Keywords:
STORMcell deathinnate immunitypathogen-associated molecular patternsignal transduction

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