A recent discovery has highlighted a new function for a cell’s own RNA in protecting against RNA virus attacks. Researchers found that certain RNA molecules within cells assist in regulating antiviral signals, which are crucial for coordinating immune responses to viral threats. Given the increasing recognition of RNA as both a therapeutic agent and a target for drug development, these findings pave the way for RNA-based treatments that could help tackle infections and autoimmune diseases.
Recent research has revealed an important new role for a cell’s own RNA in defending against RNA viruses. Scientists discovered that specific RNA molecules in cells assist in regulating antiviral signaling, which is essential for the complex orchestration of immune responses to viral invasions.
This week, a paper published in Science details how cellular RNA can perform its role in controlling infections.
“As RNA is increasingly viewed as both a therapeutic agent and a target for treatment,” the researchers noted, “this opens up possibilities for RNA-based therapies to fight both infections and autoimmune disorders.”
Dr. Ram Savan, a professor of immunology at the University of Washington School of Medicine in Seattle, led the study, with Nandan S. Gokhale, a Helen Hay Whitney and NIH Pathway to Independence Postdoctoral Fellow in Savan’s lab, serving as the principal investigator. Collaborators from the University of Washington and Duke University also contributed to the research.
Dr. Savan explained that certain proteins in the body act as guardians. When they detect RNA viruses, these proteins activate interferons through the mitochondrial antiviral signaling (MAVS) pathway. The MAVS protein is located on the outer membrane of the cell’s mitochondria, which are the energy-producing components of the cell.
When the guardian proteins identify viral RNA, MAVS proteins create platforms for other signaling proteins to attach. These large, self-assembled molecular complexes known as signalosomes facilitate protein-protein interactions and activate immune signals. The MAVS signalosomes send out alarm signals that trigger interferons and other antiviral agents, initiating various defenses against the viruses.
“While the interactions and modifications of proteins are essential for antiviral signaling through the MAVS signalosome,” stated Dr. Savan, “our research emphasizes the key role of cellular RNA molecules in this mechanism. We pinpoint specific host RNAs and proteins crucial for effectively regulating interferons.”
The researchers highlighted that this antiviral response requires a delicate balance—it must be potent enough to eliminate viruses without causing harm to tissues or triggering autoimmune conditions. Previous research has linked excessively active interferon pathways to diseases like lupus and other autoimmune disorders.
Prior to this study, it was understood that RNA interactions could alter the functions of protein complexes in various ways—such as acting as guides, chaperones, or structural supports.
However, the process of how RNA impacts the formation and function of immune signaling was not yet understood. The researchers from UW and Duke aimed to investigate how cellular RNA affects mitochondrial antiviral signaling proteins when they bind.
Their experiments indicated that cellular RNA might assist in activating the MAVS signalosome following the detection of viral RNA by the cell’s guardian proteins.
Furthermore, they discovered that MAVS directly binds to host RNA and interacts with it through a flexible region of the MAVS protein. These interactions could enhance the ability of host RNA to modulate the factors required for an optimal antiviral response.
The researchers identified which proteins interacted with MAVS with and without RNA-degrading enzyme treatment, allowing them to determine the proteins that had increased or decreased interactions with MAVS in the presence of RNA. They subsequently screened these proteins to determine which ones contributed to interferon induction and were necessary to limit viral replication.
Ultimately, the researchers established that their experiments validated a role for cellular RNA in enhancing the functions of the MAVS signalosome and, consequently, antiviral signaling. These findings provide new insights into how MAVS signaling is regulated and hint at the potential for RNA to govern other immune signaling protein complexes as well.
