Zika virus (ZIKV) has recently emerged as a global health concern owing to its widespread diffusion and its association with severe neurological symptoms and microcephaly in newborns1. However, the molecular mechanisms that are responsible for the pathogenicity of ZIKV remain largely unknown. Here we use human neural progenitor cells and the neuronal cell line SK-N-BE2 in an integrated proteomics approach to characterize the cellular responses to viral infection at the proteome and phosphoproteome level, and use affinity proteomics to identify cellular targets of ZIKV proteins. Using this approach, we identify 386 ZIKV-interacting proteins, ZIKV-specific and pan-flaviviral activities as well as host factors with known functions in neuronal development, retinal defects and infertility. Moreover, our analysis identified 1,216 phosphorylation sites that are specifically up- or downregulated after ZIKV infection, indicating profound modulation of fundamental signalling pathways such as AKT, MAPK–ERK and ATM–ATR and thereby providing mechanistic insights into the proliferation arrest elicited by ZIKV infection. Functionally, our integrative study identifies ZIKV host-dependency factors and provides a comprehensive framework for a system-level understanding of ZIKV-induced perturbations at the levels of proteins and cellular pathways.
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The mass-spectrometry-based proteomics data were deposited at the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the PRIDE partner repository with the following dataset identifiers: PXD009551, PXD009557, PXD009560 and PXD009561. The protein interactions from this publication have been submitted to the IMEx (http://www.imexconsortium.org) consortium through IntAct38 with the identifier IM-26452.
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We thank D. Mauceri, F. Sacco and L. Chatel-Chaix for discussions and R. Hornberger, I. Paron, K. Mayr and G. Sowa for technical assistance. The work in the authors’ laboratory was funded by an ERC starting grant (StG 311339, iVIP), the Max-Planck free-floater program, the German Research Foundation (PI1084/2, PI1084/3, PI1084/4, TRR 237 and TRR179) and the Federal Ministry for Education and Research (ERA-Net grant ERASe) all to A.Pi. R.B. was supported by the Deutsche Forschungsgemeinschaft (BA1505/8-1). A. Pł. was supported by the Horizon 2020: Marie Skłodowska-Curie ETN “ANTIVIRALS” (grant agreement 642434 to R.B.). M.G. was supported by the DFG (SFB871) and the advanced ERC grant ChroNeuroRepair.
Nature thanks B. Berninger, I. M. Cristea, M. Evans and J. MacKenzie for their contribution to the peer review of this work.