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.
journal_name
Cell Stem Celljournal_title
Cell stem cellauthors
Liang Q,Luo Z,Zeng J,Chen W,Foo SS,Lee SA,Ge J,Wang S,Goldman SA,Zlokovic BV,Zhao Z,Jung JUdoi
10.1016/j.stem.2016.07.019subject
Has Abstractpub_date
2016-11-03 00:00:00pages
663-671issue
5eissn
1934-5909issn
1875-9777pii
S1934-5909(16)30214-4journal_volume
19pub_type
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