Scientists identify an ion channel used by viruses to infect host cells

15/06/2018

Researchers from the Department of Biochemistry and Molecular Biology of the UAB and Pompeu Fabra University have unravelled a mechanism used by viruses to infect cells by formally identifying the interaction between an ion channel and an RNA helicase. The study has been published in Nature Communications.

Viruses are very limited in their own ability to replicate and are totally dependent upon host cell proteins for propagation. In order to infect, viruses bind to receptors on the surface of target cells, enter the cells and hijack host cell machinery to achieve their own ends. One type of cell protein that serves multiple roles in viral infections is RNA helicases.

Ion channels are cell surface proteins that regulate the permeation of ions through the cellular membranes. The flow of ions through the channels modifies electrical signals in the cells and causes rapid changes in the concentration of intracellular second messengers, such as calcium, that control different cellular functions.

One of these channels, the TRPV4, is an interesting channel to study because it responds to a diverse array of chemical and physical stimuli. Because of this gating promiscuity, TRPV4 serves as a versatile sensor that allows individual cells and the entire organism to detect changes in their environment. 

In this study published in Nature Communications, the research team discovered that the RNA helicase DDX3X interacts with the TRPV4 channel. DDX3X is involved in almost all aspects of RNA metabolism that occur both at the nucleus and the cytoplasm, and is also required for virus replication. Accordingly, DDX3X has been shown to translocate between the cytoplasm and the nucleus, although the mechanisms regulating this process is not well understood.

Therefore, the researches sought to characterize the functional significance of the interaction between TRPV4 and DDX3X and whether such interaction had any relevance in virus infection. “We have now identified that the TRPV4 channel is also capable of detecting the presence of viral proteins, thereby allowing the influx of calcium into the cell and the movement of DDX3X into the cell nucleus”, explains Pau Doñate, post-doc at the Molecular Physiology Lab and first author of the article.

Over the past years there have been unexpected illnesses and epidemics among humans generated by emerging Dengue, Zika, West Nile and Chikungunya viruses. These RNA viruses are capable of rapid mutation and selecting new variants in the face of environmental changes, hindering the identification of viral targets for pharmacological treatment and the control of epidemics.

However, as viruses are totally dependent upon host cell proteins for replication, it is of paramount importance to discover novel cell proteins and signalling pathways required for viral infection that may be viable targets for drug therapy regimens.

This approach has the advantage of targeting cellular proteins that are not subject to the rapid mutation rates seen for virus genomes. “Precisely, our finding that genetics of pharmacological inhibition of the TRPV4 channel reduced infection by Dengue, Zika and Hepatitis C viruses, opens new lines of research for therapeutic possibilities to tackle these virus infections”, says Valverde.

"This research allows us better to understand how our epithelial cells detect external stimuli, and at the same time defines new drug targets which open up an array of possibilities in preventing and treating such important viral infections such as Dengue, Zika and Hepatitis C", concludes UAB researcher Alex Perálvarez.