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Zika Virus NS4A and NS4B Proteins Deregulate Akt-mTOR Signaling in Human Fetal Neural Stem Cells to Inhibit Neurogenesis and Induce Autophagy

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Qiming Liang
  • Zhifei Luo
  • Jianxiong Zeng
  • Weiqiang Chen
  • Suan-Sin Foo
  • Shin-Ae Lee
  • Jianning Ge
  • Su Wang
  • Goldman, Steven Alan
  • Berislav V Zlokovic
  • Zhen Zhao
  • Jae U Jung

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.

OriginalsprogEngelsk
TidsskriftCell Stem Cell
Vol/bind19
Udgave nummer5
Sider (fra-til)663-671
Antal sider9
ISSN1934-5909
DOI
StatusUdgivet - 3 nov. 2016

ID: 164972167