Sensing and sensibility: the role of non-coding RNAs in autoinflammation and viral infection

Abstract

This dissertation explores the critical role of non-coding RNAs in antiviral defense and autoinflammatory disorders. Human cells have mechanisms to distinguish self RNA from viral RNA. Our findings highlight the complexity of these processes. In Aicardi-Goutières syndrome (AGS), this distinction fails: the body identifies its own RNA as viral, causing a chronic type I interferon (IFN) response. Various genetic defects can lead to this, including mutations in ADAR1, which modifies self RNA to avoid recognition. We found that the RNA receptor LGP2 is pivotal in the inflammatory response triggered by ADAR1 deficiency. LGP2 detects unmodified RNAs together with MDA5 and induces a type I IFN response. Identifying LGP2’s central role in excessive interferon production in ADAR1 deficiency is important, as it provides new approaches for targeted AGS therapies. This dissertation also investigates vault (vt)RNAs, a group of non-coding RNAs that typically fulfill regulatory functions. During viral infections, however, viruses “hijack” vtRNAs and manipulate their expression to support viral replication. These fundamental findings form the basis for novel therapies aimed at refining immune responses. By understanding how non-coding RNAs can exert both protective and harmful effects, these results pave the way for new treatment strategies for viral infections and autoinflammatory diseases.