Identification of antiviral roles for the exon-junction complex and nonsense-mediated decay in flaviviral infection

Nat Microbiol. 2019 Jun;4(6):985-995. doi: 10.1038/s41564-019-0375-z. Epub 2019 Mar 4.


West Nile virus (WNV) is an emerging mosquito-borne flavivirus, related to dengue virus and Zika virus. To gain insight into host pathways involved in WNV infection, we performed a systematic affinity-tag purification mass spectrometry (APMS) study to identify 259 WNV-interacting human proteins. RNA interference screening revealed 26 genes that both interact with WNV proteins and influence WNV infection. We found that WNV, dengue and Zika virus capsids interact with a conserved subset of proteins that impact infection. These include the exon-junction complex (EJC) recycling factor PYM1, which is antiviral against all three viruses. The EJC has roles in nonsense-mediated decay (NMD), and we found that both the EJC and NMD are antiviral and the EJC protein RBM8A directly binds WNV RNA. To counteract this, flavivirus infection inhibits NMD and the capsid-PYM1 interaction interferes with EJC protein function and localization. Depletion of PYM1 attenuates RBM8A binding to viral RNA, suggesting that WNV sequesters PYM1 to protect viral RNA from decay. Together, these data suggest a complex interplay between the virus and host in regulating NMD and the EJC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology*
  • Capsid Proteins
  • Carrier Proteins
  • Codon, Nonsense
  • Dengue Virus / genetics
  • Exons
  • Flavivirus Infections / drug therapy*
  • Host-Pathogen Interactions / drug effects
  • Host-Pathogen Interactions / genetics
  • Host-Pathogen Interactions / physiology
  • Humans
  • Protein Interaction Maps
  • RNA Interference
  • RNA, Viral
  • RNA-Binding Proteins
  • Viral Proteins / genetics*
  • Viral Proteins / physiology
  • West Nile virus / drug effects*
  • West Nile virus / genetics*
  • West Nile virus / pathogenicity
  • Zika Virus / genetics


  • Antiviral Agents
  • Capsid Proteins
  • Carrier Proteins
  • Codon, Nonsense
  • RBM8A protein, human
  • RNA, Viral
  • RNA-Binding Proteins
  • Viral Proteins