The TRPV4 channel links calcium influx to DDX3X activity and viral infectivity

Nat Commun. 2018 Jun 13;9(1):2307. doi: 10.1038/s41467-018-04776-7.

Abstract

Ion channels are well placed to transduce environmental cues into signals used by cells to generate a wide range of responses, but little is known about their role in the regulation of RNA metabolism. Here we show that the TRPV4 cation channel binds the DEAD-box RNA helicase DDX3X and regulates its function. TRPV4-mediated Ca2+ influx releases DDX3X from the channel and drives DDX3X nuclear translocation, a process that involves calmodulin (CaM) and the CaM-dependent kinase II. Genetic depletion or pharmacological inhibition of TRPV4 diminishes DDX3X-dependent functions, including nuclear viral export and translation. Furthermore, TRPV4 mediates Ca2+ influx and nuclear accumulation of DDX3X in cells exposed to the Zika virus or the purified viral envelope protein. Consequently, targeting of TRPV4 reduces infectivity of dengue, hepatitis C and Zika viruses. Together, our results highlight the role of TRPV4 in the regulation of DDX3X-dependent control of RNA metabolism and viral infectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Calcium / metabolism*
  • Calcium Signaling
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism*
  • Dengue Virus / genetics
  • Dengue Virus / pathogenicity
  • Dengue Virus / physiology
  • HeLa Cells
  • Hepacivirus / genetics
  • Hepacivirus / pathogenicity
  • Hepacivirus / physiology
  • Humans
  • Models, Biological
  • Protein Biosynthesis
  • RNA, Viral / genetics
  • RNA, Viral / metabolism
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism*
  • Two-Hybrid System Techniques
  • Virulence / genetics
  • Virulence / physiology
  • Virus Replication / genetics
  • Virus Replication / physiology
  • Zika Virus / genetics
  • Zika Virus / pathogenicity
  • Zika Virus / physiology

Substances

  • RNA, Viral
  • TRPV Cation Channels
  • TRPV4 protein, human
  • DDX3X protein, human
  • DEAD-box RNA Helicases
  • Calcium