RRC ID 47477
Author Li G, Poulsen M, Fenyvuesvolgyi C, Yashiroda Y, Yoshida M, Simard JM, Gallo RC, Zhao RY.
Title Characterization of cytopathic factors through genome-wide analysis of the Zika viral proteins in fission yeast.
Journal Proc Natl Acad Sci U S A
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.
Volume 114(3)
Pages E376-E385
Published 2017-1-17
DOI 10.1073/pnas.1619735114
PII 1619735114
PMID 28049830
PMC PMC5255628
MeSH Cell Cycle / genetics Cell Death / genetics Cell Proliferation / genetics Genome, Viral / genetics* Genome-Wide Association Study / methods Hypertrophy / genetics Membrane Proteins / genetics Oxidative Stress / genetics Promoter Regions, Genetic / genetics Schizosaccharomyces / virology* Viral Nonstructural Proteins / genetics* Zika Virus / genetics* Zika Virus Infection / virology
IF 9.412
Times Cited 27
DNA material S. pombe YFP-FLAG-His tag clone SpYFH26B06 (SPW090430) SpYFH35F03 (SPW094123) SpYFH29D03 (SPW091675).