The Zika virus NS5 protein binds HSP90 to suppress EGF-induced Akt signaling and trophoblast cell migration

Abstract

Zika virus (ZIKV) is an emerging flavivirus that causes fetal infection and congenital Zika disease, including fetal death and growth restriction. The placenta is a critical barrier at the maternal-fetal interface mostly comprised of specialized cells known as trophoblast cells. Trophoblasts respond to developmental signaling molecules such as epidermal growth factor (EGF) to migrate into the maternal decidua and mediate implantation and fetal development. EGF activates the Akt protein kinase, a master regulator of trophoblast cell migration, during the early stages of pregnancy. Akt signaling and stability are dependent on heat shock protein 90 (HSP90) which mediates client protein maturation and stability. Here we show that ZIKV infection inhibits EGF-mediated Akt phosphorylation/activation and downstream signaling to suppress EGF-induced trophoblast cell migration. The ZIKV nonstructural protein 5 (NS5) was sufficient for inhibition of trophoblast migration through binding to HSP90, suppressing Akt phosphorylation, and inhibiting EGF-induced trophoblast migration. Thus, ZIKV targets the maternal-fetal interface by inhibiting HSP90 in trophoblast cells and suppressing Akt activity, which could negatively impact placental development. Our study reveals that NS5/HSP90 interactions play a key role in ZIKV infection during pregnancy to disrupt trophoblast function and placental development leading to fetal disease.