Unlocking the power of MDA5 protein modifications in antiviral defense (2025)

Cleveland Clinic virology researchers have found that a specific protein modification to the immune protein MDA5 is key to how human bodies detect and respond to viruses and viral replication.

ThePNASpublication explains how two protein modifications activate MDA5, an essential immune protein, to sense invaders, limit viral replication and fight infections. This process is key to preventing outcomes like virus-induced heart inflammation.

This most recent publication builds on a body of work from the lab ofMichaela Gack, PhD,scientific director of Cleveland Clinic'sFlorida Research & Innovation Center, that seeks to improve our understanding of how bodies detect viruses. The team's long-term goal is to potentially translate these findings to anti-viral treatments that can combat multiple viruses.

Protein modifications are extra molecules or chemical groups added to a protein after it is made. Genes provide instructions to create proteins molecule-by-molecule, but the molecule isn't finished after that process is complete.

Cellular enzymes then add new pieces to the protein to set them up for certain functions or flag the protein for destruction. These protein modifications allow our bodies to regulate certain processes – or stop them entirely.

MDA5 is a protein involved in the very first step of how human bodies detect viruses. There are specific sites in MDA5 where protein modification occurs as part of the first step of responding to a virus. A small protein called ISG15 attaches to these sites – a process termed ISGylation, explains the study's first author Lucky Sarkar, PhD, a postdoctoral researcher in Dr. Gack's lab.

To explore how critical this specific protein modification is to sensing viruses, researchers worked with theCase Western Reserve Transgenic and Targeting Facilityto create a preclinical model harboring a version of MDA5 that lacked the sites necessary to attach to ISG15.

"Eliminating the protein's ability to be modified had almost the same effect as deleting it altogether," Dr. Sarkar said. "The data demonstrates that MDA5's ISG15 modification is key to activatinginnate immunity– our body's first line of defense."

Without MDA5 ISGylation, preclinical models of encephalomyocarditis virus (EMCV) infection were more severe. Viral replication and heart inflammation increased significantly.

Previous work from Dr. Gack's Lab has shown that MDA5 senses many other families of viruses including coronaviruses and mosquito-transmitted diseases.

We have demonstrated that MDA5 uses ISGylation to sense viral invaders once they enter our bodies. MDA5 ISGylation is a pivotal mechanism that helps our immune system to respond to a wide range of viruses. Understanding these fundamental processes behind how the body detects an intruder is critical to designing broadly antiviral treatments."

Dr.Michaela Gack, PhD,scientific director of Cleveland Clinic'sFlorida Research & Innovation Center

Drs. Gack and Sarkar say their findings could represent the first step to developing a broad-spectrum antiviral. Current research on combatting viruses mainly focuses on virus-specific vaccines or antiviral treatments, Dr. Gack explains. While these are excellent tools to prevent specific infections, they are tailor-made for each virus or even only one strain of a virus.

"Right now, we are asking if we can modulate these protein modifications to boost our natural innate immune response for the development of a broadly antiviral approach for multiple viral infections," Dr. Gack says. "That would be a game-changer for new pathogens, and for situations where traditional approaches have failed."