A decoy receptor antagonizes interferon mediated antiviral responses in teleost fish

Negative regulation of interferon (IFN) responses is crucial for preventing IFN-induced cellular damage and restoring immune homeostasis after viral clearance. However, whether such regulation occurs at the receptor level has not been explored in lower vertebrates. Here we characterized a decoy receptor (CRFB15) in zebrafish, belonging to the cytokine receptor family B, that functions as a decoy receptor to antagonize IFN-mediated signaling. CRFB15 was shown to be upregulated upon viral infection. It bound to IFN ligands and suppressed STAT1 phosphorylation and downstream antiviral effector gene expression, ultimately promoting viral replication. It also interacted with IFN receptors, including CRFB1, CRFB2, and CRFB5, selectively promoting degradation of CRFB2 and CRFB5 and attenuating IFN-induced antiviral response. Furthermore, crfb15 −/− zebrafish exhibited enhanced resistance to viral infection, confirming its role as a negative regulator of IFN signaling. This study establishes CRFB15 as a key negative regulator of teleost type I IFN signaling. Upon viral infection, CRFB15 is upregulated and suppresses IFN signaling through two distinct pathways: by functioning as a decoy receptor that competitively binds type I IFNs and their functional receptors, and/or by promoting the degradation of the key receptor subunits CRFB2 and CRFB5.