An interferon-like off-switch in invertebrates: Vago4 downregulates Domeless to restrain JAK/STAT signaling

Whether invertebrates possess a functional interferon (IFN)-like system remains controversial, as canonical IFN ligands and their receptors are absent from invertebrate genomes. Although Vago proteins in Drosophila and shrimp are compelling functional analogs of IFN, direct evidence for a canonical cytokine-receptor axis and, importantly, for how such signaling is restrained to prevent excessive immune activation, has been lacking. Here, we identify Vago4 as a bona fide ligand of Domeless, the canonical type I cytokine receptor upstream of JAK/STAT signaling. Vago4 binds the extracellular CBM1 and CBM2 domains of Domeless, triggering receptor endocytosis followed by lysosomal trafficking and K27-linked ubiquitination-dependent proteasomal degradation. This ligand-induced receptor downregulation serves as a negative feedback mechanism that restrains excessive JAK/STAT activation. During acute Vibrio infection, Vago4 silencing accelerated shrimp mortality, whereas recombinant Vago4 alleviated inflammatory lesions and oxidative stress, enhanced phagocytosis, and improved survival, phenocopying JAK or STAT knockdown. Thus, by downregulating Domeless, Vago4 limits immunopathology and defines an IRF-Vago4-Domeless-JAK/STAT IFN-like axis in invertebrates, offering new insight into the evolution of IFN-mediated immune regulation.