The innate immune system serves as the body’s primary defense against invading pathogens such as bacteria and viruses. A crucial protein involved in combating RNA viruses, including influenza, coronaviruses, and Zika virus, is TRIM25. Recent research has illuminated how TRIM25 interacts with viral RNA and the significance of this interaction for its role in antiviral defense.
Every second of our lives, we’re under assault from various threats. These threats include viruses, bacteria, parasites, and toxins—both living and non-living entities that can disrupt our body’s normal functions. Our protection comes from a team of vigilant superheroes—proteins that constitute a vital component of our innate immune system, serving as the body’s first line of defense against these invaders.
Researchers from EMBL Heidelberg have made strides in unraveling the mechanisms by which TRIM25, one of these superhero proteins, activates its powers to combat viruses.
“We were motivated to investigate TRIM25 because of its essential role in the immune response to RNA viruses like influenza and Zika,” stated Lucía Álvarez, the lead author of the study and a postdoctoral fellow in EMBL’s Hennig Group. “Our goal was to clarify how TRIM25’s ability to bind RNA contributes to its antiviral function.”
TRIM25 is part of a broad family of enzymes that can modify other proteins by adding a small molecule known as ubiquitin, which changes their activity. Its unique ability allows it to initiate a cascade of signaling events that help identify and eliminate foreign invaders. Although previous studies confirmed that TRIM25 can bind to RNA, the importance of this binding for its immune function was still uncertain.
TRIM25 also encounters a significant challenge, likened to searching for a needle in a haystack, given that our cells are filled with RNA, most of which is crucial for normal cellular functions. So, does TRIM25 have a method to differentiate between helpful and harmful RNA, allowing it to specifically target viral RNA?
To explore this question, the researchers utilized a combination of biophysical and cell biology techniques. “Our findings show that TRIM25 does not indiscriminately bind to all types of RNA,” Álvarez noted. “It has distinct preferences, which may clarify how it efficiently targets certain areas of viral RNA.”
The researchers also discovered that TRIM25’s interaction with viral RNA is vital for its antiviral functions and its ability to locate ‘factories’ within the cell where the virus replicates. To test this, they engineered a mutant version of TRIM25 that could not bind RNA. Cells expressing this ‘faulty’ form of TRIM25 were less capable of responding to infections caused by the Sindbis virus—a type of RNA virus transmitted from mosquitoes to animals.
The study, which was published recently in the journal Nature Communications, was conducted in collaboration with Alfredo Castello’s group at the Centre for Virus Research in Glasgow, alongside close cooperation with Fred Allain’s team at ETH Zurich.
“This project would not have been feasible without the support of the EIPOD4 grant and the infection biology transversal theme (IBTT) synergy grant, which facilitated my travels from EMBL to CVR and allowed our groups to work together effectively,” Álvarez added.
Looking forward, the researchers intend to explore whether the RNA-binding capability of TRIM25 is important not only for combating the Sindbis virus but also for defending against other RNA viruses. They are collaborating with Julia Mahamid’s group at EMBL Heidelberg to utilize cryo-electron tomography for a detailed examination of viral replication sites within cells where TRIM25 accumulates. A recent grant from the German Research Foundation, co-submitted by both research groups, will support this initiative.
“TRIM25 is crucial for our body’s response to viruses, including influenza, dengue, and coronaviruses,” remarked Janosch Hennig, an EMBL Visiting Group Leader and the senior author of the study. “By enhancing our understanding of TRIM25’s mechanisms, we might develop strategies to boost this immune response, and it could serve as a target for antiviral treatments. Additionally, this research could be beneficial for broader studies on RNA-binding proteins and innate immunity, potentially revealing similar processes in other proteins or immune pathways.”
