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

P Doñate-Macián,J Diez,F Rubio-Moscardo,M A Valverde,A Perálvarez-Marín,G Pérez-Vilaró,J Jungfleisch

doi:10.1038/s41467-018-04776-7

P Doñate-Macián, J Diez + Show 5 more

Open Access

https://doi.org/10.1038/s41467-018-04776-7

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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.

Highlights

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
Within this category we focused on DDX3X, an ATP-dependent RNA helicase from the DEAD-box helicase family[8,26] involved in multiple stages of the RNA metabolism, from transcription to translation[27]
No translocation of DDX3X occurred, not even in the presence of ionomycin to force global Ca2+ influx (Fig. 3d, e). These results suggested that a specific transient receptor potential vanilloid 4 (TRPV4)-induced Ca2+ nano/microdomain generated in the proximity of the complex formed by TRPV4 and DDX3X is required to promote the translocation of DDX3X to the nucleus

Summary

Introduction

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. We show that the TRPV4 cation channel binds the DEAD-box RNA helicase DDX3X and regulates its function. The calcium-permeable nonselective transient receptor potential vanilloid 4 (TRPV4) cation channel is widely expressed, shows certain spontaneous activity, and generates intracellular Ca2+ signals in response to several stimuli, including hypotonic cell swelling, mechanical forces, moderate heat and UVB radiation[17,18,19,20,21]. We set out to examine the interaction between the DDX3X helicase and the TRPV4 cation channel and how that interaction is relevant to different DDX3X functions, those related to viral RNA translation and multiplication

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Conclusion