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

Abstract

ABSTRACT 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. IMPORTANCE The expression of circVPS13D was upregulated with SCRV invasion, which proved that circVPS13D was involved in the regulation of the antiviral immune response. Our study revealed that the existence of circVPS13D promoted the replication of SCRV. Functionally, circVPS13D negatively regulates the antiviral responses of fish. Mechanistically, we confirmed that circVPS13D inhibited RLRs antiviral signaling pathway via the encoded protein VPS13D-170aa by targeting MAVS. Our study provided novel insights into the roles of protein-coding circRNAs and supported VPS13D-170aa as a negative regulator in the antiviral immune responses of teleost fish.