Two overlapping domains of a lyssavirus matrix protein that acts on different cell death pathways.
The lyssavirus matrix (M) protein induces apoptosis. The regions of the M protein that are essential for triggering cell death pathways are not yet clearly defined. We therefore compared the M proteins from two viruses that have contrasting characteristics in terms of cellular apoptosis: a genotype 3 lyssavirus, Mokola virus (MOK), and a genotype 1 rabies virus isolated from a dog from Thailand (THA). We identified a 20-amino-acid fragment (corresponding to positions 67 to 86) that retained the cell death activities of the full-length M protein from MOK via both the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and inhibition of cytochrome c oxidase (CcO) activity. We found that the amino acids at positions 77 and 81 have an essential role in triggering these two cell death pathways. Directed mutagenesis demonstrated that the amino acid at position 77 affects CcO activity, whereas the amino acid at position 81 affects TRAIL-dependent apoptosis. Mutations in the full-length M protein that compromised induction of either of these two pathways resulted in delayed apoptosis compared with the time to apoptosis for the nonmutated control.
Larrous
Florence
F
Institut Pasteur, Unité Dynamique des lyssavirus et adaptation à l'hôte, 75724 Paris Cedex 15, France.
Gholami
Alireza
A
Mouhamad
Shahul
S
Estaquier
Jérôme
J
Bourhy
Hervé
H
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D004285:Dogs; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors; D006367:HeLa Cells; D054884:Host-Pathogen Interactions / Q000502:physiology; D006801:Humans; D018114:Lyssavirus / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011820:Rabies virus / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology; D014763:Viral Matrix Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*
D017931:DNA Primers; D004279:DNA, Viral; D010446:Peptide Fragments; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014763:Viral Matrix Proteins; D003576:Electron Transport Complex IV