title: Genetic adaptation to untranslated region-mediated enterovirus growth deficits by mutations in the nonstructural proteins 3AB and 3CD.
abstract: Both untranslated regions (UTRs) of plus-strand RNA virus genomes jointly control translation and replication of viral genomes. In the case of the Enterovirus genus of the Picornaviridae family, the 5'UTR consists of a cloverleaf-like terminus preceding the internal ribosomal entry site (IRES) and the 3' terminus is composed of a structured 3'UTR and poly(A). The IRES and poly(A) have been implicated in translation control, and all UTR structures, in addition to cis-acting genetic elements mapping to the open reading frame, have been assigned roles in RNA replication. Viral UTRs are recognized by viral and host cell RNA-binding proteins that may co-determine genome stability, translation, plus- and minus-strand RNA replication, and scaffolding of viral replication complexes within host cell substructures. In this report, we describe experiments with coxsackie B viruses with a cell type-specific propagation deficit in Sk-N-Mc neuroblastoma cells conferred by the combination of a heterologous IRES and altered 3'UTR. Serial passage of these constructs in Sk-N-Mc cells yielded genetic adaptation by mutations within the viral nonstructural proteins 3A and 3C. Our data implicate 3A and/or 3C or their precursors 3AB and/or 3CD in a functional complex with the IRES and 3'UTR that drives viral propagation. Adaptation to neuroblastoma cells suggests an involvement of cell type-specific host factors or the host cell cytoplasmic milieu in this phenomenon.
authors.affiliation: Division of Neurological Surgery, Department of Surgery, Duke University Medical Center, Box 3020, Durham, NC 27710, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Florez de Sessions
authors.forename: Elena
authors.initials: E
authors.lastname: Dobrikova
authors.forename: Matthias
authors.initials: M
authors.lastname: Gromeier
mesh_terms: D000086042:3C Viral Proteases; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D029822:Enterovirus B, Human / Q000235:genetics / Q000502:physiology*; D016679:Genome, Viral / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009690:Nucleic Acid Conformation; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020506:Untranslated Regions / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D012367:RNA, Viral; D020506:Untranslated Regions; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases