Multimerization of Zika Virus-NS5 Causes Ciliopathy and Forces Premature Neurogenesis

• Published in: Cell stem cell Vol. 27; no. 6; pp. 920 - 936.e8
• Main Authors: Saade, Murielle, Ferrero, Diego S., Blanco-Ameijeiras, José, Gonzalez-Gobartt, Elena, Flores-Mendez, Marco, Ruiz-Arroyo, Victor M., Martínez-Sáez, Elena, Ramón y Cajal, Santiago, Akizu, Naiara, Verdaguer, Nuria, Martí, Elisa
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.12.2020
• Subjects: centrosome; ciliopathy; CNS growth; microcephaly; neural progenitor cell; Zika virus; microcephaly; Zika virus; centrosome; neural progenitor cell; CNS growth; ciliopathy
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2020.10.002

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. Although the enzymatic activity of ZikV-NS5 appears to be dispensable, the amino acids Y25, K28, and K29 that are involved in NS5 oligomerization are essential for localization and interaction with components of the cilium base, promoting ciliopathy and premature neurogenesis. These findings lay the foundation for therapies that target ZikV-NS5 multimerization and prevent the developmental malformations associated with congenital Zika syndrome. [Display omitted] •ZikV-NS5 interacts with and depletes centrosome proteins at the primary cilia in NPCs•ZikV-NS5 at the centrosome causes ciliopathy and promotes neuron delamination•Multimeric arrangement of ZikV-NS5 is required for nuclear exit and for ciliopathy•In human fetal brain, ZikV affects motile cilia integrity in ependymal cells Monociliated NPC proliferation ensures normal brain growth. The NS5 protein encoded by Zika virus interacts with host proteins at the cilia base, such as CEP164; induces ciliopathy; and promotes neurogenesis. Following primary neurogenesis, NPCs differentiate into multiciliated ependymal cells in which ZikV-NS5 depletes CEP164, provoking ciliopathy and ependymal layer disorganization.