TY - JOUR T1 - The cellular NMD pathway restricts Zika virus infection and is targeted by the viral capsid protein JF - bioRxiv DO - 10.1101/290296 SP - 290296 AU - Fontaine, KA AU - Leon, KE AU - Khalid, MM AU - Jimenez-Morales, D AU - Dunlap, M AU - Kaye, JA AU - Shah, PS AU - Finkbeiner, S AU - Krogan, NJ AU - Ott, M Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/04/01/290296.abstract N2 - Zika virus (ZIKV) infection of neural progenitor cells (NPCs) in utero is associated with neurological disorders, such as microcephaly1, but a detailed molecular understanding of ZIKV-induced pathogenesis is lacking. Here we show that in vitro ZIKV infection of human cells, including NPCs, causes disruption of the nonsense-mediated mRNA decay (NMD) pathway. NMD is a cellular mRNA surveillance mechanism that is required for normal brain size in mice2–4. Using affinity purification-mass spectrometry, we identified multiple cellular NMD factors that bind to the viral capsid protein, including the central NMD regulator up-frameshift protein 1 (UPF1)5. Endogenous UPF1 interacted with the viral capsid protein in co-immunoprecipitation experiments and capsid expression post-transcriptionally downregulated UPF1, a process that we confirmed occurs during de novo ZIKV infection. A further decrease in UPF1 levels by RNAi significantly enhanced ZIKV infection in NPC cultures. We therefore propose that ZIKV, via the capsid protein, has evolved a strategy to dampen antiviral activities of NMD6,7, which subsequently contributes to neuropathology in vivo. ER -