title: Conserved residues in Lassa fever virus Z protein modulate viral infectivity at the level of the ribonucleoprotein.
abstract: Arenaviruses are negative-strand RNA viruses that cause human diseases such as lymphocytic choriomeningitis, Bolivian hemorrhagic fever, and Lassa hemorrhagic fever. No licensed vaccines exist, and current treatment is limited to ribavirin. The prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV), is a model for dissecting virus-host interactions in persistent and acute disease. The RING finger protein Z has been identified as the driving force of arenaviral budding and acts as the viral matrix protein. While residues in Z required for viral budding have been described, residues that govern the Z matrix function(s) have yet to be fully elucidated. Because this matrix function is integral to viral assembly, we reasoned that this would be reflected in sequence conservation. Using sequence alignment, we identified several conserved residues in Z outside the RING and late domains. Nine residues were each mutated to alanine in Lassa fever virus Z. All of the mutations affected the expression of an LCMV minigenome and the infectivity of virus-like particles, but to greatly varying degrees. Interestingly, no mutations appeared to affect Z-mediated budding or association with viral GP. Our findings provide direct experimental evidence supporting a role for Z in the modulation of the activity of the viral ribonucleoprotein (RNP) complex and its packaging into mature infectious viral particles.
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697, USA.
authors.forename: Althea A
authors.initials: AA
authors.lastname: Capul
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: de la Torre
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Buchmeier
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D017124:Conserved Sequence; D006801:Humans; D007836:Lassa virus / Q000502:physiology*; D008954:Models, Biological; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*; D019065:Virus Assembly
chemical_list: D002352:Carrier Proteins; D050505:Mutant Proteins; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; D014763:Viral Matrix Proteins; D037521:Virulence Factors; C487631:protein Z, Lassa virus