An arms race under RIG-I loss: 5’ppp-RNA and its alternative recognition receptor MDA5

Abstract

The incessant arms race between viruses and hosts has led to numerous evolutionary innovations that shape the evolution of life. During this process, the interactions between viral receptors and viruses have garnered significant interest since viral receptors are cell surface proteins exploited by viruses to initiate infection. To further understand the interaction between viruses and receptors, our study sheds light on the arms race between the MDA5 receptor and 5’ppp-RNA in vertebrates. Firstly, the frequent and independent loss events of RIG-I in vertebrates prompted us to search for alternative immune substitutes, with homology-dependent genetic compensation response (HDGCR) being the main pathway. Our further analysis suggested that MDA5, the homolog of RIG-I, can replace RIG-I in recognizing 5’ppp-RNA and bind STING for signal transduction, which may lead to redundancy of RIG-I and loss from the species genome during evolution. Secondly, as an adversarial strategy, 5’ppp-RNA SCRV can utilize the m 6 A methylation mechanism to degrade MDA5 and weaken its antiviral immune ability, thus promoting its own replication and immune evasion. In summary, our study has revealed the molecular mechanisms underlying the interaction and coevolution between vertebrate and virus, which providing valuable insights into the ecological and evolutionary factors that contribute to the diversity of the immune system.