CircYthdc2 generates polypeptides through two translation strategies to facilitate virus escape

It is known that about 10 circular RNAs (circRNAs) can encode functional polypeptides in higher mammals. However, it is not clear whether the functional polypeptides that can be translated by circRNAs are only the products of the evolution of higher animals, or also widely exist in other lower organisms. In addition, it is also unclear whether the two ways of translating polypeptides using IRES and m⁶A in the one circRNA are exclusive or coexistent. Here, we discovered a novel circRNA derived from the 3'-5' RNA helicase Ythdc2 (Ythdc2) gene in lower vertebrate fish, namely circYthdc2, which can translate into a 170 amino acid polypeptide (Ythdc2-170aa) through IRES sequence or m⁶A modification, and is involved in antiviral immune of fish. Moreover, SCRV infection can promote circYthdc2 translate Ythdc2-170aa. Then, we found that both Ythdc2-170aa and Ythdc2 can promote the degradation of STING by promoting the ubiquitination modification of K11 and K48 link of STING, and weaken the host's antiviral innate immunity. Notably, when circYthdc2 is abundant, Ythdc2 preferentially degrades circYthdc2 and no longer promotes the degradation of STING. Further studies have shown that circYthdc2 is highly conserved from lower vertebrates to higher mammals, and human circYthdc2 can also encode the same polypeptide and play a similar function to that of fish circYthdc2. This discovery confirms for the first time that the ability of circRNA to encode functional proteins is evolutionarily conserved, and finds that the ways of polypeptide translation by the same circRNA were diverse, which is of great significance for further elucidating the function and evolution of circRNAs in vertebrates.