Identification of a type I IFN- and IRF-inducible enhancer in the 5′-UTR intron of MAVS in large yellow croaker Larimichthys crocea

Abstract

The mitochondrial antiviral signaling protein (MAVS) relays signals from RIG-I-like receptors (RLRs) to induce type I interferon (IFN) production. In teleost fish, MAVS expression is significantly upregulated in response to viral infections or synthetic double-stranded RNA (dsRNA), whereas mammalian MAVS does not exhibit a similar response. However, the mechanisms regulating MAVS expression in teleosts remain unclear. In this study, we demonstrate that the viral mimic poly(I:C)-induced upregulation of Larimichthys crocea (Lc) MAVS occurs via the type I IFN signaling pathway. Inhibition of the JAK-STAT pathway significantly suppressed both poly(I:C)- and LcIFNi-induced LcMAVS expression. Further analysis revealed that an enhancer in the 5′- untranslated region (UTR) intron of LcMAVS contains two functional interferon-stimulated response elements (ISREs), which are crucial for its activation. The enhancer activity of LcMAVS is regulated by interferon regulatory factors (IRFs), including IRF1, IRF3, IRF7, IRF9, and IRF11. These IRFs form several heterodimeric complexes, such as IRF1/3, IRF1/7, IRF3/7, and IRF3/11, to mediate LcMAVS enhancer activation. Structural analysis indicates that the ISRE motifs in the intronic enhancer can accommodate two or three DNA-binding domains (DBDs) from IRFs. These findings provide a potential explanation for the differential regulation of MAVS in response to stimuli in teleosts and mammals. Furthermore, our study demonstrates that MAVS is an interferon-stimulated gene (ISG) in a marine fish, providing insights into the evolutionary divergence of the vertebrate RLR signaling pathway.