„Molecular mechanisms of nucleic acids receptors signalling regulation by Pellino 3 protein during viral infection”
(acronym: PELLINO)

Project supported by the National Science Centre, Poland under the „SONATA BIS 5” programme

Total cost: 1 994 800,00 PLN
Centre Contribution: 1 994 800,00 PLN
Duration: 22/04/2016 – 21/04/2021

Principal Investigator: dr hab. inż. Jakub Siednienko

Intracellular nucleic acid sensors play an important role in the innate immune response. This is due to the ability of these proteins to recognize and bind viral as well as bacterial RNA or DNA, then activating signaling cascades, which consequently leads to the production of IFN and/or inflammatory cytokines. The aim of this project is to characterize the regulation process of transcription and activation of the intracellular receptors (RIG-I and MDA5) able to detect the presence of RNA of viral origin which is mediated by a ubiquitin ligase Pellino3.
For efficient infection of eukaryotic cells, viruses have evolved plethora mechanisms to inactivate a specific cell receptors. For instance, US11 derived from Herpes simplex virus, a protein which binds to receptors in the helicase domain of RLR, prevents interaction of the receptor with the viral RNA. Similarly, the NS1 and NS2, RSV’s proteins, interact with RLR, wherein it was shown that NS2 binds to CARD-domain of RIG-I receptor thus preventing signal transduction protein MAVS. Other viruses, such as: Poliovirus, Rihinovirus, Echovirus or Encephalomyocarditisvirus encode C3 proteases which cut RIG-I receptor. There are also viral protein E3L (Vaccina virus), VP35 (Ebola virus), and TRS1 or M142/M143 (Human cytomegalovirus) that bind to dsRNA preventing it from being detected by the RLR. Therefore, the last years were full of research on signal transduction mediated by RLRs as well as on developing a strategy of targeted therapy that affects these signaling pathways. Despite intense attention from the scientific community focused on these receptors, not all mechanisms of action are explained.
This project aims to broaden knowledge about transmitting a signal from the cytosolic receptors, with particular emphasis on RIG-I and MDA5 and is crucial for understanding the function of the immune system. Moreover, the identification of the protein Pellino3 as a particle which plays an important role in antiviral response activated by RLRs, provides the possibility of targeted regulation of cytosolic receptors and thus response to viral infections, what is unique in the contextof the current state of art.