tetano
Editor, Senior Moderator
[h=1]Zika Virus NS4A and NS4B Proteins Deregulate Akt-mTOR Signaling in Human Fetal Neural Stem Cells to Inhibit Neurogenesis and Induce Autophagy[/h] Qiming Liang
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, Zhifei Luo
, Jianxiong Zeng
, Weiqiang Chen
, Suan-Sin Foo
, Shin-Ae Lee
, Jianning Ge
, Su Wang
, Steven A. Goldman
, Berislav V. Zlokovic
, Zhen Zhao
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, Jae U. Jung[SUP]8[/SUP][SUP],[/SUP]
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[SUP]8[/SUP]Lead Contact
Publication stage: In Press Corrected Proof
DOI: http://dx.doi.org/10.1016/j.stem.2016.07.019
[h=2]
Article Info[/h] [h=2]Highlights[/h]
[h=2]Summary[/h] 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.
full article
http://www.cell.com/cell-stem-cell/fulltext/S1934-5909(16)30214-4
Press enter key to Email the author, Zhifei Luo
, Jianxiong Zeng
, Weiqiang Chen
, Suan-Sin Foo
, Shin-Ae Lee
, Jianning Ge
, Su Wang
, Steven A. Goldman
, Berislav V. Zlokovic
, Zhen Zhao
Press enter key to Email the author, Jae U. Jung[SUP]8[/SUP][SUP],[/SUP]
Press enter key to Email the author[SUP]8[/SUP]Lead Contact
Publication stage: In Press Corrected Proof
DOI: http://dx.doi.org/10.1016/j.stem.2016.07.019
[h=2]
Article Info[/h] [h=2]Highlights[/h]- ?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
[h=2]Summary[/h] 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.
full article
http://www.cell.com/cell-stem-cell/fulltext/S1934-5909(16)30214-4