New Insights into How TRIM25 Fights RNA Viruses

Human bodies are attacked every second of every day. Invading agents include bacteria, viruses, parasites, and toxins, both living and non-living, that could impair body function. Humans' innate immune system, which is the body's initial line of defense against invaders, is made up of proteins that act as patrolling superheroes and keep them safe.

Researchers at EMBL Heidelberg have taken a significant step toward understanding how TRIM25, a critical immune protein, combats viruses. 

"We were inspired to study TRIM25 because of its essential role in the body’s immune response to RNA viruses like influenza and Zika," explains Lucía Álvarez, the study’s first author and EIPOD4 postdoctoral fellow in the Hennig Group at EMBL. "We wanted to understand TRIM25’s RNA-binding role in antiviral defense."

TRIM25, part of a family of enzymes that alter other proteins by attaching a small protein called ubiquitin, is especially powerful in triggering signaling pathways that lead to recognizing and neutralizing viruses. Although TRIM25’s ability to bind RNA had been previously shown, its significance in immune response remained unclear.

Faced with vast amounts of cellular RNA, TRIM25 must distinguish viral RNA from cellular RNA. Using cell biology and biophysical techniques, researchers found that TRIM25 selectively binds specific RNA types, which may explain how it effectively targets viral RNA regions.

They further demonstrated that TRIM25’s binding to viral RNA is essential for its antiviral activity and localization to cellular “factories” where viruses replicate. Cells with a mutant form of TRIM25, unable to bind RNA, were less effective in fighting the Sindbis virus—a mosquito-borne RNA virus.

The study, a collaboration with Alfredo Castello’s team at the Centre for Virus Research in Glasgow and Fred Allain’s group at ETH Zurich, was published in Nature Communications. Supported by the EIPOD4 and IBTT synergy grants, this project benefited from collaboration across EMBL, CVR, and ETH Zurich.

Next, researchers aim to determine whether TRIM25’s RNA binding is crucial for defense against other RNA viruses and explore its localization in viral replication organelles using cryo-electron tomography in collaboration with Julia Mahamid’s lab at EMBL Heidelberg. A recent German Research Foundation grant will support this work.

“TRIM25 plays a vital role in our body’s defense against viruses like influenza, dengue, and coronaviruses. Understanding its function could inform new antiviral strategies and broaden our insights into RNA-binding proteins and innate immunity,” says Janosch Hennig, Visiting Group Leader and study senior author at EMBL.