Zika virus induces FOXG1 nuclear displacement and down-regulation

The Zika virus (ZIKV), a Flavivirus transmitted by mosquitoes or sexually, gained global attention in 2016 due to an increase in microcephalic newborns from infected mothers. ZIKV, often asymptomatic in adults, can cause severe congenital malformations in fetuses. Despite efforts, the link between ZIKV and congenital abnormalities remains unclear. Recent research suggests similarities between fetal ZIKV infection and congenital disorders related to the FOXG1 gene. FOXG1, a vital transcription factor, plays a key role in brain development. This study aimed to investigate how ZIKV affects the subcellular localization of FOXG1. In the study were used GFP-fused Foxg1 plasmids to examine ZIKV's impact. In A549 cells and neural progenitor cells (NPCs) derived from induced pluripotent stem cells (hiPSCs), ZIKV infection led to reduced nuclear Foxg1-GFP fluorescence, specifically associated with ZIKV. Western blot analysis confirmed FOXG1 downregulation post-ZIKV infection. Selectivity for FOXG1 was evident, as other neural transcription factors remained unaffected. ZIKV-infected hiPS-NPCs showed dysregulated expression of genes associated with cell replication and apoptosis. The study delved into cellular mechanisms, focusing on Akt-mediated phosphorylation at T271 in Foxg1. Mutant Foxg1 variants revealed T271's pivotal role, influenced by ZIKV-triggered alterations in pAkt/Akt levels. The C-terminal portion of FOXG1 was identified as crucial for ZIKV-induced subcellular changes. Investigating the ZIKV protease NS2B-NS3 and growth factors (GFs), particularly FGF2, showed no direct protease activity against FOXG1, but FGF2 secretion increased following ZIKV infection. FGF2 treatment enhanced ZIKV infection in A549 cells, while GFs supplementation prevented FOXG1 displacement in ZIKV-infected cells. In summary, the study suggests that ZIKV selectively targets FOXG1, causing its export and downregulation. This involves T271 phosphorylation, Akt pathway activation, and modulation of GFs expression. These findings contribute to understanding the mechanisms leading to microcephaly in fetuses following congenital ZIKV infection.