Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Cell stem cell, 2016-11, Vol.19 (5), p.663-671

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. [Display omitted] •ZIKV infects human fNSCs, leading to defective neurogenesis and increased autophagy•Expression of ZIKV NS4A and NS4B blocks neurogenesis and promotes autophagy•Two ZIKV proteins, NS4A and NS4B, inhibit Akt-mTOR signaling Liang et al. show that after infection of human fetal neural stem cells, the ZIKV proteins NS4A and NS4B inhibit the Akt-mTOR signaling pathway, disrupting neurogenesis and inducing autophagy. Their study therefore identifies candidate molecular determinants of ZIKV pathogenesis and highlights potential targets for therapeutic intervention.