title: Characterization of cytopathic factors through genome-wide analysis of the Zika viral proteins in fission yeast.
abstract: The Zika virus (ZIKV) causes microcephaly and the Guillain-Barré syndrome. Little is known about how ZIKV causes these conditions or which ZIKV viral protein(s) is responsible for the associated ZIKV-induced cytopathic effects, including cell hypertrophy, growth restriction, cell-cycle dysregulation, and cell death. We used fission yeast for the rapid, global functional analysis of the ZIKV genome. All 14 proteins or small peptides were produced under an inducible promoter, and we measured the intracellular localization and the specific effects on ZIKV-associated cytopathic activities of each protein. The subcellular localization of each ZIKV protein was in overall agreement with its predicted protein structure. Five structural and two nonstructural ZIKV proteins showed various levels of cytopathic effects. The expression of these ZIKV proteins restricted cell proliferation, induced hypertrophy, or triggered cellular oxidative stress leading to cell death. The expression of premembrane protein (prM) resulted in cell-cycle G1 accumulation, whereas membrane-anchored capsid (anaC), membrane protein (M), envelope protein (E), and nonstructural protein 4A (NS4A) caused cell-cycle G2/M accumulation. A mechanistic study revealed that NS4A-induced cellular hypertrophy and growth restriction were mediated specifically through the target of rapamycin (TOR) cellular stress pathway involving Tor1 and type 2A phosphatase activator Tip41. These findings should provide a reference for future research on the prevention and treatment of ZIKV diseases.
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Ge
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Melissa
authors.initials: M
authors.lastname: Poulsen
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Csaba
authors.initials: C
authors.lastname: Fenyvuesvolgyi
authors.affiliation: RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yashiroda
authors.affiliation: RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201.|Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: J Marc
authors.initials: JM
authors.lastname: Simard
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201; RZhao@som.umaryland.edu rgallo@ihv.umaryland.edu.|Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201.|Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Gallo
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201; RZhao@som.umaryland.edu rgallo@ihv.umaryland.edu.|Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201.|Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Richard Y
authors.initials: RY
authors.lastname: Zhao
mesh_terms: D002453:Cell Cycle / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D016679:Genome, Viral / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D006984:Hypertrophy / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012568:Schizosaccharomyces / Q000821:virology*; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D000071244:Zika Virus / Q000235:genetics*; D000071243:Zika Virus Infection / Q000821:virology
chemical_list: D008565:Membrane Proteins; D017361:Viral Nonstructural Proteins
keywords: Schizosaccharomyces pombe; Zika genome; Zika proteins; cytopathic factors; fission yeast