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.

寨卡病毒 (ZikV) 是一种感染神经组织的黄病毒，可引起先天性小头畸形。ZikV 已经进化出多种机制来限制增殖和增强细胞死亡，尽管所涉及的潜在细胞事件仍不清楚。在这里，我们展示了 ZikV-NS5 蛋白与神经祖细胞初级纤毛底部的宿主蛋白相互作用，导致非典型的非遗传性纤毛病和神经元过早分层。此外，在人类小头胎儿脑组织中，ZikV-NS5 持续存在于室管膜细胞中运动纤毛的基部，这也表现出严重的纤毛病。尽管 ZikV-NS5 的酶活性似乎是可有可无的，但参与 NS5 寡聚化的氨基酸 Y25、K28 和 K29 对于定位和与纤毛基部成分的相互作用至关重要，促进纤毛病和过早的神经发生。这些发现为靶向 ZikV-NS5 多聚化和预防与先天性寨卡综合征相关的发育畸形的疗法奠定了基础。