Multimerization of Zika Virus-NS5 Causes Ciliopathy and Forces Premature Neurogenesis
Murielle Saade1, Diego S Ferrero2, José Blanco-Ameijeiras1
1Developmental Biology Department, Instituto de Biología Molecular de Barcelona (IBMB-CSIC), Parc Científic de Barcelona, C/Baldiri i Reixac 20, Barcelona 08028, Spain.
Abstract:
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.
Insights
Zika virus (ZikV) protein NS5 disrupts cilia in neural cells, causing developmental brain defects. Targeting NS5
Area of Science:
- Neuroscience
- Virology
- Cell Biology
Background:
- Zika virus (ZikV) is a flavivirus known to cause congenital microcephaly by infecting neural tissues.
- The precise cellular mechanisms by which ZikV induces developmental abnormalities remain incompletely understood.
- Cilia, crucial for neural development, are potential targets for viral interference.
Purpose of the Study:
- To elucidate the role of Zika virus NS5 protein in neural progenitor cells and fetal brain development.
- To investigate the interaction of ZikV-NS5 with cellular structures, particularly cilia.
- To identify potential therapeutic targets for congenital Zika syndrome.
Main Methods:
- Analysis of ZikV-NS5 protein interactions with host proteins at the base of primary cilia in neural progenitor cells.
- Examination of human microcephalic fetal brain tissue for ZikV-NS5 presence and associated ciliopathy.
- Mutagenesis studies to assess the importance of NS5 amino acids (Y25, K28, K29) in NS5 oligomerization and ciliary localization.
Main Results:
- ZikV-NS5 protein localizes to the base of primary cilia in neural progenitor cells, inducing an atypical ciliopathy and premature neuron delamination.
- ZikV-NS5 is found at the base of motile cilia in ependymal cells in human microcephalic fetal brain, correlating with severe ciliopathy.
- The enzymatic activity of ZikV-NS5 is dispensable; however, specific amino acids (Y25, K28, K29) essential for NS5 oligomerization are critical for ciliopathy induction.
Conclusions:
- Zika virus NS5 protein directly interferes with cilia function in neural cells, leading to developmental malformations characteristic of congenital Zika syndrome.
- NS5-induced ciliopathy and premature neurogenesis are linked to NS5 oligomerization and its interaction with the cilium base.
- Targeting ZikV-NS5 multimerization presents a potential therapeutic strategy to prevent Zika virus-associated developmental defects.
