RESUMEN

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.

Asunto(s)

Calcio/metabolismo , ARN Helicasas DEAD-box/metabolismo , Canales Catiónicos TRPV/metabolismo , Transporte Activo de Núcleo Celular , Señalización del Calcio , ARN Helicasas DEAD-box/genética , Virus del Dengue/genética , Virus del Dengue/patogenicidad , Virus del Dengue/fisiología , Células HeLa , Hepacivirus/genética , Hepacivirus/patogenicidad , Hepacivirus/fisiología , Humanos , Modelos Biológicos , Biosíntesis de Proteínas , ARN Viral/genética , ARN Viral/metabolismo , Canales Catiónicos TRPV/genética , Técnicas del Sistema de Dos Híbridos , Virulencia/genética , Virulencia/fisiología , Replicación Viral/genética , Replicación Viral/fisiología , Virus Zika/genética , Virus Zika/patogenicidad , Virus Zika/fisiología