Multimerization of Zika Virus-NS5 Causes Ciliopathy and Forces Premature Neurogenesis
| Autor: | Murielle Saade, Elena Gonzalez-Gobartt, Santiago Ramón y Cajal, Victor M. Ruiz-Arroyo, Elisa Martí, Diego S. Ferrero, Naiara Akizu, Elena Martínez-Sáez, Núria Verdaguer, José Blanco-Ameijeiras, Marco Flores-Mendez |
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| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Fundació La Marató de TV3, Ministerio de Ciencia, Innovación y Universidades (España), National Institutes of Health (US) |
| Rok vydání: | 2020 |
| Předmět: |
Microcephaly
Centrosomes Neurogenesis viruses Ciliopathy Viral Nonstructural Proteins Microbiology Article Zika virus 03 medical and health sciences 0302 clinical medicine Pregnancy Genetics medicine Humans Progenitor cell Pregnancy Complications Infectious Base (exponentiation) 030304 developmental biology 0303 health sciences General Immunology and Microbiology biology 030306 microbiology Zika Virus Infection Cilium virus diseases Cell Biology biology.organism_classification medicine.disease Virology humanities Ciliopathies Neural stem cell Cell biology Infectious Diseases Centrosome Neural progenitor cell Motile cilium Molecular Medicine Female CNS growth 030217 neurology & neurosurgery |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname Cell Stem Cell |
| Popis: | 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. The work in E.M.’s laboratory was supported by grants BFU2016-77498-P, BFU2016-77498-P, and La Maratò de TV3 foundation 201833-10. M.S. holds a Ramón Y Cajal fellowship (RYC2018-025379-I). J.B.-A is a recipient of a BES-2017-080050 PhD scholarship. The work in N.V.’s laboratory was supported by grants BIO2017-83906-P, Maria de Maeztu Unit of Excellence MDM-2014-0435 (MCIU), and La Maratò de TV3 foundation 201833-10. The work in N.A.’s laboratory was supported by NIH/NINDS R00NS089859 and IDDRC-NPDA (CHOP/Penn). |
| Databáze: | OpenAIRE |
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