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

Abstract

SUMMARY 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.

To Zika and Destroy: An Antimalarial Drug Protects Fetuses from Zika Infection

“…Further experiments confirmed that deletion of Atg16l1 exclusively in trophoblasts was sufficient to limit ZIKV maternal-fetal transmission. However, deletion of Atg16l1 exclusively in trophoblasts did not reduce ZIKV titers in fetal heads, supporting a previous report that autophagy plays a role in ZIKV infection of the fetal neurons [11]. Together, these findings suggest that autophagy promotes ZIKV infection in the placenta.…”

“…Our work provides a new perspective in understanding the mechanism of HCQ's anti-ZIKV effects during pregnancy. Recent studies have shown that ZIKV nonstructural proteins block the Akt-mTOR pathway in human fetal neural stem cells, which may contribute to autophagy activation as mTOR negatively regulates autophagy [11]. Future work untangling the ZIKV-autophagy interaction will help elucidate the molecular mechanism underlying why autophagy inhibition blocks ZIKV infection and maternal-fetal transmission.…”

Using brain organoids to understand Zika virus-induced microcephaly

“…A number of studies have since modeled ZIKV infection using human NPC monolayer and neurosphere cultures, acute fetal brain slices, and brain organoids (Barrows et al, 2016;Cugola et al, 2016;Dang et al, 2016;Garcez et al, 2016;Hanners et al, 2016;Liang et al, 2016;Onorati et al, 2016;Qian et al, 2016;Retallack et al, 2016;Simonin et al, 2016;Wells et al, 2016) (Fig. 1).…”

“…Therefore, it is possible to examine how an individual or combination of ZIKV-encoded proteins, or ZIKV-derived noncoding RNAs, affects brain organoid development (Liang et al, 2016). Insights into downstream molecular events will enhance our understanding of how ZIKV interacts with the host machinery to suppress NPC proliferation and induce cell death, as well as help to identify genes and pathways necessary for ZIKV replication .…”

Dengue and Zika viruses subvert reticulophagy by NS2B3-mediated cleavage of FAM134B

“…[11][12][13][14] Several flaviviruses, including DENV and ZIKV, potently induce autophagy, which allows for efficient viral replication and virion assembly. [15][16][17][18][19][20][21][22] Interestingly, DENV infection relies on selective autophagy of lipid droplets (lipophagy) to provide energy required for viral replication. 15 A number of other forms of selective autophagy have been described including degradation of ribosomes (ribophagy), peroxisomes (pexophagy), mitochondria (mitophagy), and ER (reticulophagy).…”