New research from scientists at the University of Washington (UW) School of Medicine and Duke University describes how cellular RNA helps regulate antiviral signaling as part of the immune response against viral infections. Details are published in a new Science paper titled, “Cellular RNA interacts with MAVS to promote antiviral signaling.” The scientists say that the findings highlight the potential for developing RNA-based therapeutics that target infections and autoimmunity.
Before this study, researchers knew that RNA interactions could modify protein complexes by serving as guides, chaperones, or scaffolds. What was unclear was how RNA influences the formation and function of immune signaling. As Ram Savan, PhD, senior investigator on the study and professor of immunology at UW School of Medicine, explained, “While protein-protein interactions and protein modifications are critical for antiviral signaling through the MAVS signalosome, our research highlights the significant role of cellular RNA molecules in this process. We identify specific host RNA and proteins necessary for the effective regulation of interferons.”
Digging into the details, some proteins act as guards by activating interferons through the mitochondrial antiviral signaling (MAVS) pathway. The MAVS protein resides on the outer mitochondrial membrane. When these guard proteins sense viral RNA, MAVS proteins combine with other signaling proteins to form signalosomes. These are large, self-assembled molecular complexes that support protein-protein interactions and send transcription factors to activate interferons and other antiviral factors that mount various defenses against viruses. The response has to be managed carefully so that it is strong enough to clear out viruses without sparking an autoimmune response. Previous studies have shown implicated overactive interferon-inducing pathways in lupus and other autoimmune conditions.
Among other findings, the team demonstrated that MAVS proteins bind to host RNA directly and interact directly with cellular RNA through a disordered region of the protein. And they suspect that these interactions may strengthen the host RNA modulation of factors needed to maximize the antiviral response.
To identify which guard proteins interact with MAVS, researchers assessed interactions in the presence or absence of enzymes that degrade RNA. They picked proteins with more or fewer interactions with MAVS in the presence of RNA and screened them to see which helped induce interferon and were required to restrict viral replication.
Overall, these results confirm a role for cellular RNA in promoting the function of the MAVS signalosome and antiviral signaling. And they point to the possibility of additional instances of RNA regulating other immune signaling protein complexes.
