A novel protein encoded by circVPS13D attenuates antiviral innate immunity by targeting MAVS in teleost fish.

The signaling adaptor MAVS is a vital adaptor protein in retinoic acid-inducible gene I-like receptors (RLRs) signaling; thus, its expression and responses must be tightly regulated to avoid uncontrolled production of type I IFN by various mechanisms, including ubiquitination. The protein-coding ability of circRNAs has recently been a hot topic, but the roles of protein-coding circRNAs in antiviral innate immunity of teleost have rarely been reported. In this study, we identify that a novel circRNA derived from vacuolar protein sorting-associated protein 13D (VPS13D) gene, named circVPS13D, was a suppressor of RLR signaling pathways during poly(I:C) stimulation or Siniperca chuatsi rhabdovirus (SCRV) infection. Mechanistically, circVPS13D contains a 513-nucleotide (nt) open reading frame (ORF) and a sequence that is -174 nt as an internal ribosome entry site (IRES), which is required for translation initiation in 5'-cap-independent coding RNAs. SCRV infection promoted the expression of circVPS13D and circVPS13D encodes a novel peptide, termed VPS13D-170 amino acid (aa), which directly interacted with MAVS and inhibited IFN-I production. VPS13D-170aa targeted the K172 residue of MAVS through K48-linked polyubiquitination, leading to proteasomal degradation of MAVS. [ABSTRACT FROM AUTHOR]