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The Secret Role of RNA in Boosting Our Immune Defenses

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When you pick up a virus, your immune system has to recognize the invader before it can launch its defenses and keep the virus from spreading. One key player in this battle is a protein called Mitochondrial antiviral signaling protein (MAVS). MAVS works with other proteins to recognize RNA viruses like a first responder and tells the body to activate immune signaling pathways. But a new study has found MAVS don’t act alone, they get critical help from an unexpected source: cellular RNA.

To find out how and if RNA helps MAVs mount an immune response, researchers treated cells with RNase-a chemical that degrades RNA-and measured the activity of the MAVS and the proteins that are known to help MAVs recognize a virus and start the immune response. Usually, MAVS activates transcription factors such as IRF3 and NF-κB, which go to the cell’s DNA and help turn on genes that make proteins to fight the virus. But when RNA was degraded, the transcription factors weren’t as active. These findings showed that RNA was not just a passive bystander but an active participant required for the proper functioning of MAVS.

MAVS Sticky Connection to RNA

MAVS has a flexible region called an “intrinsically disordered domain,” which can interact with a wide array of molecule types, including RNA. Their flexibility lets them bind to many different RNA molecules, similar to how objects cling to sticky surfaces. The researchers used infrared dye crosslinking and immunoprecipitation techniques to uncover this interaction. In infrared dye crosslinking, a special dye is attached to the MAVS protein; when it binds to RNA, the dye acts to “mark” this interaction by emitting infrared light, allowing researchers to track the binding. While immunoprecipitation uses antibodies that are made to only bind to MAVS. Researchers can use the antibody to pull out the MAVS and isolate anything an MAVS is binding to, like RNA. Using these techniques, the researchers were able to demonstrate that MAVS binds to more than 100 cellular mRNAs, including mRNAs that encode proteins important for antiviral defense.

Striking a Balance: Amplifying and Regulating the Immune Response

While RNA helps to amplify MAVS activity, it also plays a role in dampening the immune response by facilitating interactions with both positive and negative regulators of MAVS to prevent overactivation, which can cause damage to the body. The balance of this was uncovered using mass spectrometry. The technique allows researchers to look at proteins present in a sample and compare interacting proteins with MAVS in the presence or absence of RNA. In the presence of RNA, MAVS interacts with proteins such as GPX8, which reduces cell stress, and ZNF622, which regulates gene activity. Showing RNA is essential for helping MAVS signal the body to produce antiviral defenses like interferons. Others, like ANKLE2, act as brakes to keep the immune system from overreacting and causing harm. The researchers also found that when they turned off genes like GPX8 and ZNF622, the immune response was weaker, showing that MAVS is important to help improve antiviral signaling. This study showed how RNA helps MAVS strike a balance between fighting viruses and preventing damage to the body.

*MAVS recruits RNA to initiate an antiviral defense in cells. Image made by author in* *Biorender.com*

This discovery reveals a new regulatory role for RNA in immune signaling, opening potential avenues for new therapies. For example, drugs designed to enhance RNA’s ability to activate MAVS might help boost the immune system’s battle against viruses.

The fight between your immune system and invading viruses is complex — RNA is not just a messenger, but it’s a key partner in the detection and response against viral infections. Teaming up with MAVS, RNA amplifies the immune system’s signals, opening up ways for future treatment to help your body defend itself from invaders.

Link to the original post: Nandan S. Gokhale et al. ,Cellular RNA interacts with MAVS to promote antiviral signaling. Science 386,eadl0429(2024).

Featured image: Made by author in Canva.com