Human being induced pluripotent stem cell derived neural progenitor cells (hNPCs, HIP Human Neural Stem Cells, MTI GlobalStem Cat# GSC-4311; a gift of Dr . ribosomal stress may contribute to neuronal death, neurodevelopmental disruption and microcephaly. == Introduction == Zika computer virus (ZIKV) is a mosquito-transmitted RNA virus that belongs to the computer virus familyFlaviviridaeand causes usually asymptomatic infection in humans1. However , a causative link continues to be established between prenatal exposure to ZIKV and severe congenital microcephaly1. ZIKV ability to disturb neurodevelopment is consistent with a neurotropic potential of other arthropod-transmitted flaviviruses1. For instance, mosquito-transmitted West Nile virus (WNV) and Japanese encephalitis computer virus (JEV) infect CNS neurons causing neurological diseases which may include neuronal loss and permanent deficits in brain function2. However , ZIKV appears to be a uniquely potent brain teratogen1. Such effect is likely due to its ability to penetrate the placenta and infect fetal brain3. In contrast, innate anti-viral response may prevent ZIKV from reaching the brain in adults. Congenital microcephaly is caused by insufficiency of neurogenesis that may originate from (i) depletion of neuroprogenitor cells (NPCs) due to their apoptosis and/or pre-mature differentiation, (ii) inhibition of NPC proliferation, and, (iii) apoptosis of newly generated neurons46. ZIKV has a large potential to infect human or rodent NPCs and to a lesser extent developing neurons711. ZIKV reduces NPC proliferation, induces their premature differentiation and activates apoptosis of Aminophylline NPCs and immature neurons. However , a question remains as to what are the mechanisms behind such cytotoxic effects of ZIKV. Recent work has suggested that ZIKV protein NS4A and, to lesser extent, NS4B may impair NP proliferation by inhibiting the growth promoting AKT pathway12. In addition , Tp53 continues to be proposed to mediate ZIKV-induced apoptosis but its ZIKV-related activation mechanism remains obscure13. Thus, experiments are needed to determine which ZIKV proteins induce cell death of the developing brain cells and what the mechanisms behind their anti-survival effects in this cellular context are. Although flaviviruses replicate on the ER membrane14, 15, at least a fraction of some flaviviral proteins is found in the nucleus from the infected cells, including nucleolar presence of WNV-, JEV-, or Dengue virus (DENV) capsid protein (protein C)16. Being structural components of flaviviruses, capsid proteins are very abundant in the infected cells17. They interact with multiple host proteins including ribosomal biogenesis factors (RBFs)1821. Some of these interactions may be toxic to the infected cells. For instance, immature form of WNV-C was shown to cause nucleolar sequestration from the Tp53 inhibitor MDM2/HDM2 leading to Tp53-mediated apoptosis in a human being cell line22. The nucleolus, where flaviviral capsid proteins are often discovered, is a center of ribosomal biogenesis23. Dysregulation of ribosomal biogenesis triggers ribosomal stress (RS)24. In most cases, such a response relies on interactions between the Tp53 ubiquitin ligase MDM2/HDM2 Aminophylline and ribosomal components that are no longer incorporated into ribosomes24. Specifically, RPL11, RPL5, and 5S rRNA, behaving as a complex (the 5S ribonucleoprotein particle /5S RNP/), bind and inhibit MDM2, stabilizing Tp53 and generating cell cycle arrest and/or apoptosis25, 26. When RNA-Polymerase-1 (Pol1), which initiates ribosomal biogenesis, is inhibited, nucleolar structure is disrupted23. Thus, loss of the granular component (GC) from the nucleolus including nucleoplasmic dispersion of its prominent protein components such as nucleophosmin-1 (NPM1/B23) or PES1 provides a convenient way of monitoring this type of ALPP RS27. However , the RS-Tp53 pathway may also be activated without structural disruption from the nucleolus and with normal- or increased activity of Pol127, 28. Several lines of evidence suggest that RS may be involved in pathogenesis of neurodevelopmental diseases. First, RS activates RPL11/Tp53-dependent apoptosis of immature cortical neurons29. Second, acephalic mouse fetuses were produced when Pol1 was inhibited selectively in Nestin-positive NPCs30. Similarly, just a single injection of the anti-ribosomal drug 5-fluorouracil to pregnant rats induces microcephaly from the offspring31. Finally, recent description of the nucleolar proteome from the developing rat brain included 9 proteins whose human being counterparts are mutated in microcephaly syndromes32. Several Aminophylline of these proteins are expected to participate in brain ribosomal biogenesis as verified.