Definition of the immune evasion-replication interface of rabies virus P protein.
Animals
COS Cells
Chlorocebus aethiops
HEK293 Cells
Humans
Immune Evasion
/ physiology
Molecular Chaperones
/ metabolism
Nucleocapsid Proteins
/ metabolism
Rabies
/ metabolism
Rabies virus
/ metabolism
STAT1 Transcription Factor
/ metabolism
Viral Structural Proteins
/ metabolism
Virus Replication
/ physiology
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
02
02
2021
accepted:
18
06
2021
revised:
20
07
2021
pubmed:
9
7
2021
medline:
25
2
2023
entrez:
8
7
2021
Statut:
epublish
Résumé
Rabies virus phosphoprotein (P protein) is a multifunctional protein that plays key roles in replication as the polymerase cofactor that binds to the complex of viral genomic RNA and the nucleoprotein (N protein), and in evading the innate immune response by binding to STAT transcription factors. These interactions are mediated by the C-terminal domain of P (PCTD). The colocation of these binding sites in the small globular PCTD raises the question of how these interactions underlying replication and immune evasion, central to viral infection, are coordinated and, potentially, coregulated. While direct data on the binding interface of the PCTD for STAT1 is available, the lack of direct structural data on the sites that bind N protein limits our understanding of this interaction hub. The PCTD was proposed to bind via two sites to a flexible loop of N protein (Npep) that is not visible in crystal structures, but no direct analysis of this interaction has been reported. Here we use Nuclear Magnetic Resonance, and molecular modelling to show N protein residues, Leu381, Asp383, Asp384 and phosphor-Ser389, are likely to bind to a 'positive patch' of the PCTD formed by Lys211, Lys214 and Arg260. Furthermore, in contrast to previous predictions we identify a single site of interaction on the PCTD by this Npep. Intriguingly, this site is proximal to the defined STAT1 binding site that includes Ile201 to Phe209. However, cell-based assays indicate that STAT1 and N protein do not compete for P protein. Thus, it appears that interactions critical to replication and immune evasion can occur simultaneously with the same molecules of P protein so that the binding of P protein to activated STAT1 can potentially occur without interrupting interactions involved in replication. These data suggest that replication complexes might be directly involved in STAT1 antagonism.
Identifiants
pubmed: 34237115
doi: 10.1371/journal.ppat.1009729
pii: PPATHOGENS-D-21-00257
pmc: PMC8291714
doi:
Substances chimiques
Molecular Chaperones
0
Nucleocapsid Proteins
0
P phosphoprotein, Rabies virus
0
STAT1 Transcription Factor
0
Viral Structural Proteins
0
nucleocapsid protein, Rabies virus
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1009729Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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