Insect-borne flaviviruses produce a 300-500-base long noncoding RNA, termed 
subgenomic flavivirus RNA (sfRNA), by stalling the cellular 
5'-3'-exoribonuclease 1 (XRN1) via structures located in their 3' UTRs. In this 
study, we demonstrate that sfRNA production by Zika virus represses XRN1 
analogous to what we have previously shown for other flaviviruses. Using 
protein-RNA reconstitution and a stringent RNA pulldown assay with human 
choriocarcinoma (JAR) cells, we demonstrate that the sfRNAs from both dengue 
type 2 and Zika viruses interact with a common set of 21 RNA-binding proteins 
that contribute to the regulation of post-transcriptional processes in the cell, 
including splicing, RNA stability, and translation. We found that four of these 
sfRNA-interacting host proteins, DEAD-box helicase 6 (DDX6) and enhancer of mRNA 
decapping 3 (EDC3) (two RNA decay factors), phosphorylated adaptor for RNA 
export (a regulator of the biogenesis of the splicing machinery), and 
apolipoprotein B mRNA-editing enzyme catalytic subunit 3C (APOBEC3C, a nucleic 
acid-editing deaminase), inherently restrict Zika virus infection. Furthermore, 
we demonstrate that the regulations of cellular mRNA decay and RNA splicing are 
compromised by Zika virus infection as well as by sfRNA alone. Collectively, 
these results reveal the large extent to which Zika virus-derived sfRNAs 
interact with cellular RNA-binding proteins and highlight the potential for 
widespread dysregulation of post-transcriptional control that likely limits the 
effective response of these cells to viral infection.