title: Zika Virus NS4A and NS4B Proteins Deregulate Akt-mTOR Signaling in Human Fetal Neural Stem Cells to Inhibit Neurogenesis and Induce Autophagy.
abstract: The current widespread outbreak of Zika virus (ZIKV) infection has been linked to severe clinical birth defects, particularly microcephaly, warranting urgent study of the molecular mechanisms underlying ZIKV pathogenesis. Akt-mTOR signaling is one of the key cellular pathways essential for brain development and autophagy regulation. Here, we show that ZIKV infection of human fetal neural stem cells (fNSCs) causes inhibition of the Akt-mTOR pathway, leading to defective neurogenesis and aberrant activation of autophagy. By screening the three structural proteins and seven nonstructural proteins present in ZIKV, we found that two, NS4A and NS4B, cooperatively suppress the Akt-mTOR pathway and lead to cellular dysregulation. Corresponding proteins from the closely related dengue virus do not have the same effect on neurogenesis. Thus, our study highlights ZIKV NS4A and NS4B as candidate determinants of viral pathogenesis and identifies a mechanism of action for their effects, suggesting potential targets for anti-ZIKV therapeutic intervention.
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: liangqiming@shsmu.edu.cn.
authors.forename: Qiming
authors.initials: Q
authors.lastname: Liang
authors.affiliation: Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Zhifei
authors.initials: Z
authors.lastname: Luo
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Jianxiong
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Suan-Sin
authors.initials: SS
authors.lastname: Foo
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Shin-Ae
authors.initials: SA
authors.lastname: Lee
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Jianning
authors.initials: J
authors.lastname: Ge
authors.affiliation: Center for Translational Neuromedicine, University of Rochester, Rochester, NY 14642, USA; Department of Neurology, University of Rochester, Rochester, NY 14642, USA; Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark.
authors.forename: Su
authors.initials: S
authors.lastname: Wang
authors.affiliation: Center for Translational Neuromedicine, University of Rochester, Rochester, NY 14642, USA; Department of Neurology, University of Rochester, Rochester, NY 14642, USA; Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Goldman
authors.affiliation: Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Berislav V
authors.initials: BV
authors.lastname: Zlokovic
authors.affiliation: Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: zzhao@usc.edu.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: jaeujung@med.usc.edu.
authors.forename: Jae U
authors.initials: JU
authors.lastname: Jung
mesh_terms: D000818:Animals; D001343:Autophagy; D005333:Fetus / Q000473:pathology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology*; D055495:Neurogenesis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D000071244:Zika Virus / Q000502:physiology*; D000071243:Zika Virus Infection / Q000378:metabolism / Q000473:pathology
chemical_list: C080106:NS4A protein, flavivirus; C080107:NS4B protein, flavivirus; D017361:Viral Nonstructural Proteins; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases