Molecular Mechanisms Regulating the Activity of Intracellular Nucleic Acid Receptor Signaling Pathways by the Pellino 3 Protein in Response to Viral Infections – Pellino

Cytosolic nucleic acid receptors play a major role in the innate immune response due to their ability to recognize and bind viral and bacterial RNA or DNA, subsequently initiating signaling cascades that lead to the production of interferons (IFN) and/or pro-inflammatory cytokines. The aim of this project is to characterize the regulation of transcription and activity of intracellular receptors capable of detecting viral RNA (RIG-I and MDA5) by the ubiquitin ligase Pellino 3.

To achieve efficient infection of eukaryotic cells, viruses have evolved mechanisms for targeted deactivation of host receptors. For example, the US11 protein from Herpes simplex virus binds to RLR helicase domains, preventing the receptor from interacting with viral RNA. Similarly, the NS1 and NS2 proteins of RSV interact with RLRs; NS2 binds to the CARD domain of RIG-I, thereby blocking signal transduction to MAVS. Other viruses—including Poliovirus, Rhinovirus, Echovirus, and Encephalomyocarditis virus—encode C3 proteases that cleave the RIG-I receptor. Additional viral proteins such as E3L (Vaccinia virus), VP35 (Ebola virus), and TRS1 or m142/m143 (Human Cytomegalovirus) bind dsRNA, preventing its detection by RLRs.

For these reasons, recent years have seen intensive research into RLR signaling and into targeted therapeutic strategies that modulate these pathways. Despite considerable scientific attention, many aspects of RLR function remain unresolved. This project aims to expand current knowledge on cytosolic receptor signaling, with a particular emphasis on RIG-I and MDA5, both of which are critical for effective innate immune responses.

Moreover, the identification of Pellino 3 as a protein with an essential role in antiviral defense—and the investigation of its regulatory functions—opens the possibility for targeted modulation of cytosolic receptor regulation, and thereby modulation of antiviral responses. Given the current state of knowledge, this represents a uniquely promising research direction.