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Two overlapping domains of a lyssavirus matrix protein that acts on different cell death pathways

Florence Larrous1, Alireza Gholami, Shahul Mouhamad

  • 1Institut Pasteur, Unité Dynamique des lyssavirus et adaptation à l'hôte, 75724 Paris Cedex 15, France.

Journal of Virology
|July 16, 2010
PubMed

Insights

The lyssavirus matrix protein fragment (67-86) triggers cell death via TRAIL and CcO inhibition. Specific amino acids at positions 77 and 81 are crucial for these apoptosis pathways.

Area of Science:

  • Virology
  • Molecular Biology
  • Cell Biology

Background:

  • Lyssavirus matrix (M) proteins are known to induce apoptosis.
  • The specific regions and residues responsible for M protein-induced cell death are not fully elucidated.

Purpose of the Study:

  • To identify the regions of the lyssavirus M protein essential for inducing apoptosis.
  • To compare the apoptosis-inducing capabilities of M proteins from different lyssavirus genotypes.
  • To investigate the roles of specific amino acids in M protein-mediated cell death pathways.

Main Methods:

  • Comparative analysis of M proteins from Mokola virus (MOK, genotype 3) and a Thai rabies virus (THA, genotype 1).
  • Identification and characterization of a 20-amino-acid fragment (positions 67-86) responsible for cell death induction.
  • Site-directed mutagenesis to assess the function of amino acids at positions 77 and 81.
  • Evaluation of apoptosis induction via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and cytochrome c oxidase (CcO) activity.

Main Results:

  • A 20-amino-acid fragment (MOK M protein, positions 67-86) retained full-length M protein's cell death activities.
  • Amino acids at positions 77 and 81 were identified as critical for triggering TRAIL-dependent apoptosis and CcO inhibition, respectively.
  • Mutations affecting these pathways in the full-length M protein led to delayed apoptosis.

Conclusions:

  • The 20-amino-acid fragment (67-86) of the MOK lyssavirus M protein is sufficient to induce apoptosis through TRAIL and CcO inhibition.
  • Specific residues (77 and 81) play distinct roles in mediating these apoptosis pathways.
  • Understanding these mechanisms is vital for lyssavirus pathogenesis and therapeutic strategies.

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