Structurally defined IL-6-like cytokine candidates in bilaterian invertebrates and cnidarians 2306759

Abstract Introduction Type I (4-α-helical bundle) cytokines, including IL-6, are central to vertebrate immunity, but rapid sequence divergence obscures their evolutionary origins and has hindered the identification of homologs in non-vertebrate animals. As core JAK-STAT signaling components are conserved across invertebrates, we hypothesized that, despite extensive loss of primary sequence similarity, a protein with IL-6-like structure and inducible regulation could be conserved across invertebrates. Methods To test this hypothesis, we first screened genomic and transcriptomic resources from bilaterian invertebrates and cnidarians using deep-learning-based structural prediction, defining candidates as ∼200-aa secreted proteins with a predicted 4-helix bundle. We then assessed putative immune function by re-analyzing public RNA-seq datasets from bivalve mollusks (as representative bilaterian invertebrates) and cnidarians challenged with bacteria or subjected to nucleic acid-sensing pathway activation. Results This analysis identified a previously unrecognized family of secreted proteins whose predicted 4-helical bundles align closely with vertebrate IL-6 despite < 20% sequence identity. Transcriptomic meta-analysis revealed robust induction of these IL-6-like genes following immune stimulation in both cnidarians and mollusks. Conclusion Together, our results indicate that type I cytokine-like architectures are more widely distributed across animals than previously appreciated and support an origin predating the Cnidaria-Bilateria split. Funding Source This study was supported by National Institutes of Health Grants R01AI072435 and R35GM122591 Topic Categories Cytokines and Chemokines and their Receptors (CCR)