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

Qiming Liang, et al.

Cell Stem Cell 19, 1–9, 2016

Speaker: Ming-Yu Shieh (謝明育)                                       Time: 14:00-15:00, Nov. 23, 2016

Commentator: Dr. Guey-Chuen Perng (彭貴春老師)          Place: Room 601

Abstract:

        Zika virus (ZIKV), an arthropod-borne flavivirus, is a positive-sense and non-segmented RNA genome virus transmitted through A. aegypti and A. albopictus. ZIKV-infected humans develop a dengue-like disease with fever, red eyes, joint pain, headache, and maculopapular rash. Recently, ZIKV infection has been shown to be associated with neurological defects in newborns. Previous study showed that ZIKV infection leads to poor growth of neurospheres and brain organoids derived from iPSCs [1]. However, the molecular mechanism by which ZIKV causes microcephaly in newborns is unclear. Neurogenesis is an important differentiation process of neurons from neural stem cells (NSCs) or neural progenitor cells (NPCs) in fetal brain. PI3K-Akt-mTOR signaling is an important signal pathway for neurogenesis. Inhibition of either Akt or mTOR in the developing brains may cause microcephaly [2]. Dengue virus NS4A protein has been reported to inhibit  PI3K-Akt-mTOR signal pathway to promote autophagy for enhancing virus replication in epithelial cells [3]. Whether ZIKV uses the similar mechanism for virus replication remains unknown. In this study, the authors found impaired neurosphere formation and elevated autophagy in ZIKV-infected human fetal neural stem cells (fNSCs). ZIKV NS4A and NS4B proteins cooperatively upregulated LC3-II expression and downregulated Ki-67 expression in fNSCs. Moreover, transfection of ZIKV NS4A and NS4B proteins in fNSCs decreased GFAP and β-tubulin expression and suppressed fNSC differentiation. Inhibition of AKT phosphorylation at T308 and S473 was observed in NS4A and NS4B-transfected fNSCs. These results suggest that inhibition of neurogenesis and upregulation of autophagy in ZIKV-infected fNSCs were through the deregulation of Akt-mTOR pathway by ZIKV NS4A and NS4B proteins. ZIKV NS4A and NS4B are important factors for virus pathogenesis and serve as potential targets for anti-ZIKV therapeutic intervention.

References：

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