Multimerization of Zika Virus-NS5 causes a ciliopathy and forces premature neurogenesis
Diego S Ferrero,
Victor M. Ruiz-Arroyo,
Santiago Ramón y Cajal,
Posted 04 Aug 2019
bioRxiv DOI: 10.1101/719625 (published DOI: 10.1016/j.stem.2020.10.002)
Posted 04 Aug 2019
Zika virus (ZikV) is a flavivirus that infects neural tissues, causing congenital microcephaly. ZikV has evolved multiple mechanisms to restrict proliferation and enhance cell death, although the underlying cellular events involved remain unclear. Here we show that the ZikV-NS5 protein interacts with host proteins at the base of the primary cilia in neural progenitor cells, causing an atypical non-genetic ciliopathy and premature neuron delamination. Furthermore, in human microcephalic fetal brain tissue, ZikV-NS5 persists at the base of the motile cilia in ependymal cells, which also exhibit a severe ciliopathy. While the enzymatic activity of ZikV-NS5 appears to be dispensable, the Y25, K28 and K29 residues in the protein, that are involved in NS5-oligomerization, are essential for the localization and interaction with components of the cilium base, promoting ciliopathy and premature neurogenesis. These findings lay the foundation to develop therapies that target ZikV-NS5-multimerization, preventing the developmental malformations associated with congenital Zika syndrome.
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