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D471G mutation in LCMV-NP affects its ability to self-associate and results in a dominant negative effect in viral RNA synthesis

Academic Article
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Overview

authors

  • Ortiz-Riano, E.
  • Cheng, B. Y. H.
  • de la Torre, Juan
  • Martinez-Sobrido, L.

publication date

  • October 2012

journal

  • Viruses-Basel  Journal

abstract

  • Arenaviruses merit significant interest because several family members are etiological agents of severe hemorrhagic fevers, representing a major burden to public health. Currently, there are no FDA-licensed vaccines against arenaviruses and the only available antiviral therapy is limited to the use of ribavirin that is partially effective. Arenavirus nucleoprotein (NP) is found associated with the genomic RNA forming the viral ribonucleoproteins (vRNPs) that together with the polymerase (L) direct viral replication and transcription. Virion formation requires the recruitment of vRNPs into budding sites, a process in which the arenavirus matrix-like protein (Z) plays a major role. Therefore, proper NP-NP and NP-Z interactions are required for the generation of infectious progeny. In this work we demonstrate the role of the amino acid residue D471 in the self-association of lymphocytic choriomeningitis virus nucleoprotein (LCMV-NP). Amino acid substitutions at this position abrogate NP oligomerization, affecting its ability to mediate replication and transcription of a minigenome reporter plasmid. However, its ability to interact with the Z protein, counteract the cellular interferon response and bind to dsRNA analogs was retained. Additionally, we also document the dominant negative effect of D471G mutation on viral infection, suggesting that NP self-association is an excellent target for the development of new antivirals against arenaviruses.

subject areas

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Aspartic Acid
  • Blotting, Western
  • Carrier Proteins
  • Genes, Reporter
  • Green Fluorescent Proteins
  • HEK293 Cells
  • Humans
  • Immunoprecipitation
  • Interferon Type I
  • Lymphocytic choriomeningitis virus
  • Molecular Sequence Data
  • Mutation
  • Nucleoproteins
  • Plasmids
  • Protein Binding
  • Protein Interaction Mapping
  • RNA Replicase
  • RNA, Double-Stranded
  • RNA, Viral
  • RNA-Binding Proteins
  • Species Specificity
  • Transcription, Genetic
  • Transfection
  • Viral Proteins
  • Virus Assembly
  • Virus Replication
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Research

keywords

  • Z matrix protein
  • dominant negative
  • double-stranded RNA
  • lymphocytic choriomeningitis virus
  • minigenome
  • nucleoprotein
  • self-association
  • type I Interferon
  • viral-like particles
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Identity

PubMed Central ID

  • PMC3497045

International Standard Serial Number (ISSN)

  • 1999-4915

Digital Object Identifier (DOI)

  • 10.3390/v4102137

PubMed ID

  • 23202457
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Additional Document Info

start page

  • 2137

end page

  • 2161

volume

  • 4

issue

  • 10

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