An ancient anthozoan protein reveals an alternative evolutionary path of antiviral signaling

How antiviral immunity first arose in animals is a central question in evolutionary biology. Using the sea anemone Nematostella vectensis, we identify CARDIB, a previously uncharacterized gene located next to RLRb, a cnidarian homolog of the vertebrate RIG-I-like receptor family. This conserved genomic linkage across Anthozoa reveals an ancient coupling between immune sensing and regulation. Despite sequence similarity to vertebrate MAVS, CARDIB performs an opposing function: it represses immune genes under basal conditions yet is essential for activation upon viral challenge. CARDIB binds RLRb via a single CARD domain, forming a repressive complex. Loss of either gene abolishes antiviral transcription, disrupts apoptosis, and elevates viral load under lab conditions. Both genes as well as the RLRb paralog, RLRa, are essential for antiviral defense under native conditions. Phylogeny places the cnidarian CARDs distinctly from the vertebrate RLR-MAVS families, revealing an ancient antiviral system regulating antiviral response through CARD-based signaling.