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.
P Doñate-Macián  1  2 ,  J Jungfleisch  3 ,  G Pérez-Vilaró  3 ,  F Rubio-Moscardo  1 ,  A Perálvarez-Marín  2 ,  J Diez  3 ,  M A Valverde  4
Affiliations
  • 1. Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003, Barcelona, Spain.
  • 2. Departament de Bioquímica i de Biologia Molecular, Unitat de Biofísica, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain.
  • 3. Molecular Virology Group, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003, Barcelona, Spain.
  • 4. Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003, Barcelona, Spain. [email protected].
PMID: 29899501 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.