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A positive-feedback mechanism promotes reovirus particle conversion to the intermediate associated with membrane

Melina A Agosto1, Kimberly S Myers, Tijana Ivanovic

  • 1Department of Microbiology and Molecular Genetics, Harvard Medical School, and Training Programs in Biological and Biomedical Sciences and Virology, Division of Medical Sciences, Harvard University, Boston, MA 02115, USA.

Proceedings of the National Academy of Sciences of the United States of America
|July 26, 2008
PubMed

Insights

Reovirus membrane penetration involves particle conversion. A positive-feedback mechanism, driven by released mu1N peptide, promotes this conversion, a process crucial for viral entry.

Area of Science:

  • Virology
  • Molecular Biology
  • Biophysics

Background:

  • Reovirus entry into cells involves the conversion of an intermediate particle (ISVP) to a more disassembled form (ISVP*).
  • Factors regulating this critical conversion step in cellular environments remain largely unknown.

Purpose of the Study:

  • To investigate the in vitro mechanisms that promote the conversion of reovirus ISVP to ISVP*.
  • To characterize a potential positive-feedback loop in viral particle disassembly.

Main Methods:

  • In vitro kinetic analysis of reovirus ISVP conversion at varying particle concentrations.
  • Biochemical assays to identify the promoting factors released during conversion.
  • Characterization of a reovirus mutant unable to release the mu1N peptide.

Main Results:

  • Reovirus ISVP conversion exhibits second-order kinetics at high particle concentrations, indicating a cooperative mechanism.
  • The released pore-forming peptide mu1N is sufficient to promote ISVP* conversion in trans.
  • A mutant lacking mu1N release failed to show second-order kinetics or promote wild-type ISVP conversion.
  • Promotion of conversion is temperature-dependent and linked to target ISVP stability, suggesting capsid dynamics are involved.

Conclusions:

  • A novel positive-feedback mechanism enhances reovirus ISVP* conversion, mediated by released mu1N peptide.
  • This mechanism allows reovirus to sense and respond to confined cellular environments during entry.
  • This positive-feedback strategy for viral escape from metastable states may be generalizable to other viruses.

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