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

Vago4 is identified as a bona fide ligand for Domeless in shrimp, downregulating the receptor to restrain JAK/STAT signaling and limit immunopathology.

• Why it matters: Invertebrates lack canonical interferon ligands and receptors, leaving unclear whether an IFN-like cytokine–receptor axis exists and how it is kept from overactivating immunity.
• What they did: The study shows Vago4 binds Domeless extracellular CBM1/CBM2, promoting receptor endocytosis, lysosomal trafficking, and K27-linked ubiquitination–dependent proteasomal degradation.
• The result: During acute Vibrio infection, Vago4 silencing accelerated shrimp mortality, while recombinant Vago4 reduced inflammatory lesions and oxidative stress, boosted phagocytosis, and improved survival, phenocopying JAK or STAT knockdown.

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