Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003, Barcelona, Spain.
Departament de Bioquímica i de Biologia Molecular, Unitat de Biofísica, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain.
Nat Commun. 2018 Jun 13;9(1):2307. doi: 10.1038/s41467-018-04776-7.
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 Ca 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 Ca 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.
离子通道在将环境线索转导为细胞用来产生广泛反应的信号方面具有得天独厚的优势，但它们在调节 RNA 代谢中的作用知之甚少。在这里，我们表明 TRPV4 阳离子通道与 DEAD 盒 RNA 解旋酶 DDX3X 结合并调节其功能。TRPV4 介导的 Ca2+内流将 DDX3X 从通道中释放出来，并驱动 DDX3X 核转位，这一过程涉及钙调蛋白 (CaM) 和 CaM 依赖性激酶 II。TRPV4 的遗传缺失或药理学抑制会减弱 DDX3X 依赖的功能，包括核病毒输出和翻译。此外，TRPV4 介导细胞暴露于寨卡病毒或纯化的病毒包膜蛋白时 DDX3X 的 Ca2+内流和核积累。因此，TRPV4 的靶向作用降低了登革热、丙型肝炎和寨卡病毒的感染性。总之，我们的研究结果强调了 TRPV4 在调节 DDX3X 依赖性 RNA 代谢和病毒感染性的控制中的作用。
