close
close

The cellular superhero who protects us again

Picture:

A new study has examined the RNA binding mechanisms of the antiviral protein TRIM25. TRIM25 (green, left) finds its way to the same places in the cell where a virus (red, middle) replicates. The image to the right shows how the two intersect.

view more

Photo credit: Lucía Álvarez and Daniela Velasco/EMBL

Our bodies are under attack every second of every day. The invading pathogens are viruses, bacteria, parasites and toxins – living and non-living entities that can have a negative impact on the functioning of our bodies. What protects us is a group of patrolling superheroes – proteins that form an essential part of our innate immune system, the body's first line of defense against invaders.

A new study Heidelberg researchers at EMBL have brought us one step closer to understanding how one such superhero – a protein called TRIM25 – uses his superpowers to fight viruses.

“We were inspired to study TRIM25 because it plays a crucial role in the body's innate immune response to RNA viruses such as influenza or Zika viruses,” said Lucía Álvarez, the study's first author and EIPOD4 Postdoctoral researcher at EMBL Hennig group. “We wanted to understand the role of TRIM25 RNA binding in antiviral defense.”

TRIM25 belongs to a large family of enzymes that can mark other proteins in the cell with a small protein called ubiquitin, changing their function. His superpower is the ability to trigger a series of signaling events that ultimately result in the foreign agent being identified and neutralized. While scientists had previously shown that TRIM25 could bind RNA, it was not clear why this effect was important for its immune activity.

TRIM25 also faces the proverbial needle in a haystack – after all, our cells swim in RNA, a large part of which is essential for our biology and function. So does TRIM25 have a way to distinguish friend from foe and selectively bind to RNA derived from viruses?

To investigate this question in more detail, the scientists used a combination of biophysical and cell biological techniques. “We found that TRIM25 doesn’t just bind to any RNA randomly,” said Álvarez. “It has specific preferences that could explain how it efficiently targets regions of viral RNA.”

The scientists also found that this binding to viral RNA is crucial to TRIM25's antiviral activity, as well as its ability to find its way to “factories” within the cell where the virus makes copies of itself. To test this, the researchers created a mutated version of TRIM25 that was unable to bind RNA. Cells with this “defective” version of TRIM25 were less effective at fighting infection by Sindbis virus – an RNA virus that can be transmitted from mosquitoes to vertebrates.

The study was recently published in the diary Nature communicationwas carried out in collaboration with Alfredo Castello's group at the Center for Virus Research (CVR) in Glasgow. The researchers also worked closely with Fred Allain's group at ETH Zurich.

“This project was made possible by the EIPOD4 grant and that Synergy grant for the Infection Biology Transversal Theme (IBTT).which allowed me to move from EMBL to CVR to benefit from the synergies between the groups,” said Álvarez.

In the next step, the researchers are investigating whether RNA binding of TRIM25 is important not only for the Sindvis virus, but also for the defense against other RNA viruses. The team also works together Julia Mahamid's group at EMBL Heidelberg to use cryo-electron tomography to take a closer look at the viral replication organelles in the cells where TRIM25 is localized. A grant from the German Research Foundation recently submitted jointly by the two groups will make this part of the work possible.

“TRIM25 plays a key role in our body’s response to viruses such as influenza, dengue and coronaviruses,” said Janosch Hennig, EMBL visiting group leader and senior author of the study. “By better understanding how TRIM25 works, we may be able to develop strategies to enhance this immune response, making it a potential target for antiviral therapies. “In addition, the study could be applied to broader research on RNA-binding proteins and innate immunity and help uncover similar mechanisms in other proteins or immune pathways.”


Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of press releases published on EurekAlert! by contributing institutions or for the use of any information via the EurekAlert system.