Human Sec3 protein is a novel transcriptional and translational repressor of flavivirus

The Flaviviridae family consists of several medically important pathogens such as West Nile virus (WNV) and Dengue virus (DENV). Flavivirus capsid (C) protein is a key structural component of virus particles. However, the role of C protein in the pathogenesis of arthropod-borne flaviviruses is poorly understood. To examine whether flavivirus C protein can associate with cellular proteins, and contribute to viral pathogenesis, WNV/DENV C protein was screened against a human brain/liver cDNA yeast two-hybrid library. This study identified human Sec3 exocyst protein (hSec3p) as a novel interacting partner of WNV and DENV C protein. Mutagenesis studies showed that the SH2 domain-binding motif of hSec3p binds to the first 15 amino acids of C protein. We report for the first time that hSec3p can modulate virus production by affecting viral RNA transcription and translation through the sequestration of elongation factor 1alpha (EF1alpha). This molecular discovery shed light on the protective role of hSec3p during flavivirus infection. This study also highlighted the antagonistic mechanism adopted by flavivirus C protein that can negatively regulate the formation of hSec3p-EF1alpha complex by sequestering hSec3p to establish successful infection.