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Characterization of Multi-subunit Protein Complexes of Human MxA Using Non-denaturing Polyacrylamide Gel-electrophoresis
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Characterization of Multi-subunit Protein Complexes of Human MxA Using Non-denaturing Polyacrylamide Gel-electrophoresis

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Oligomerization and GTP-binding Requirements of MxA for Viral Target Recognition and Antiviral Activity against

Patricia E Nigg1, Jovan Pavlovic2

  • 1From the Institute of Medical Virology, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.

The Journal of Biological Chemistry
|October 29, 2015
PubMed

Insights

Human myxovirus resistance protein A (MxA) restricts influenza A virus (IAV) replication. Dimeric MxA binds viral nucleoprotein, inhibiting IAV, suggesting MxA

Area of Science:

  • Virology
  • Molecular Biology
  • Immunology

Background:

  • Human myxovirus resistance protein A (MxA) is an interferon-induced GTPase with broad antiviral activity, including against influenza A virus (IAV).
  • MxA's antiviral mechanism and whether it acts in monomeric or multimeric forms are not fully understood.
  • MxA self-assembles into various structures, including dimers and tetramers, complicating mechanistic studies.

Purpose of the Study:

  • To elucidate the molecular mechanism of MxA's antiviral activity against IAV.
  • To determine if MxA exerts antiviral effects in monomeric or multimeric forms.
  • To investigate the role of MxA oligomerization in its interaction with IAV nucleoprotein (NP).

Main Methods:

  • Utilized MxA mutants with defined stoichiometry to study protein assembly and disassembly.
  • Employed guanosine 5'-O-(thiotriphosphate) to induce MxA disassembly.
  • Conducted infection experiments with wild-type and mutant MxA, assessing IAV replication and MxA-NP complex formation.

Main Results:

  • MxA disassembled into dimers and tetramers in the presence of guanosine 5'-O-(thiotriphosphate); dimers did not further dissociate into monomers.
  • Dimeric and monomeric MxA variants effectively restricted IAV replication post-primary transcription.
  • Only dimeric MxA formed stable complexes with IAV nucleoprotein (NP), with differential binding to sensitive versus resistant strains.

Conclusions:

  • MxA disassembles into active dimers during infection, which bind to viral NP after primary transcription.
  • This interaction between dimeric MxA and NP inhibits viral replication.
  • The findings reveal a specific mechanism for MxA-mediated antiviral defense against IAV.
Keywords:
GTPaseMx proteinantiviral agentinfluenza virusinnate immunityinterferonnucleoproteinprotein assembly

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