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 - KA Fontaine AU - KE Leon AU - MM Khalid AU - D Jimenez-Morales AU - S Tomar AU - M Dunlap AU - JA Kaye AU - PS Shah AU - S Finkbeiner AU - NJ Krogan AU - M Ott Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/05/19/290296.abstract N2 - Zika virus (ZIKV) infection of neural progenitor cells (NPCs) in utero is associated with neurological disorders, such as microcephaly1–3, 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 mice4–6. 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)7. 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. RNA electrophoretic mobility shift assays with UPF1-expressing cell lysates showed binding to ZIKV RNA in vitro, and UPF1 protein in ZIKV-infected NPCs colocalized with viral double-stranded RNA replication intermediates. Collectively, our data support a model where ZIKV, via the capsid protein, has evolved a strategy to dampen antiviral activities of NMD8,9, which subsequently contributes to neuropathology in vivo. ER -