Neurodevelopmental protein Musashi-1 interacts with the Zika genome and promotes viral replication
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AbstractA recent outbreak of Zika virus in Brazil has led to a simultaneous increase in reports of neonatal microcephaly. Zika targets cerebral neural precursors, a cell population essential for cortical development, but the cause of this neurotropism remains obscure. Here we report that the neural RNA-binding protein Musashi-1 (MSI1) interacts with the Zika genome and enables viral replication. Zika infection disrupts the binding of MSI1 to its endogenous targets, thereby deregulating expression of factors implicated in neural stem cell function. We further show that MSI1 is highly expressed in neural progenitors of the human embryonic brain, and is mutated in individuals with autosomal recessive primary microcephaly. Selective MSI1 expression in neural precursors could therefore explain the exceptional vulnerability of these cells to Zika infection.
The authors are indebted to Alain Kohl (Centre for Virus Research, University of Glasgow) and Lindomar J. Pena and Rafael Oliveira de Freitas França, Fiocruz Recife, Pernambuco, Brazil, for the provision of PE243 ZIKV RNA used to generate the virus stock. We would like to thank and acknowledge Steve Lisgo for the expert provision of human embryonic histology sections through the Human Developmental Biology Resource (HDBR) at the University of Newcastle funded by a joint UK MRC/Wellcome Trust grant (099175/Z/12/Z). We would like to thank Leanna Smith for her assistance with homology modeling, Guillaume van Zande for his help and the patients’ families for their participation. The National Research Ethics Service Committee, East of England - Cambridge Central, UK (C.G. Woods, REC 05/Q0108/402) approved the informed consent to enter the study. We are grateful for expert help by the CRUK CI Core Facilities. I.G. and A. E. F are Wellcome Trust Senior Fellows. I.G. was supported by research grants 097997/Z/11/A and 097997/Z/11/Z, whereas A. E. F by grant 106207. M.S.N was funded by the Wellcome Trust (200183/Z/15/Z) and T. R. S is a Wellcome Trust Henry Dale Fellow (202471/Z/16/Z). This work was made possible by funding from Cancer Research UK C14303/A17197 to FG and C24461/A12772 to R.B. F.G. and C.G.W. acknowledge support from NIHR Cambridge Biomedical Research Centre, the University of Cambridge and Hutchison Whampoa Ltd.