Antimicrobial peptides (AMPs) are host-encoded antibiotics that combat invading pathogens. These genes commonly encode multiple products as post-translationally cleaved polypeptides. Recent studies have highlighted roles for AMPs in neurological contexts suggesting functions for these defence molecules beyond infection. During our immune study characterizing the antimicrobial peptide gene Baramicin, we recovered multiple Baramicin paralogs in Drosophila melanogaster and other species, united by their N-terminal IM24 domain. Not all paralogs were immune-induced. Here, through careful dissection of the Baramicin family's evolutionary history, we find that paralogs lacking immune induction result from repeated events of duplication and subsequent truncation of the coding sequence from an immune-inducible ancestor. These truncations leave only the IM24 domain as the prominent gene product. Surprisingly, using mutation and targeted gene silencing we demonstrate that two such genes are adapted for function in neural contexts in D. melanogaster. We also show enrichment in the head for independent Baramicin genes in other species. The Baramicin evolutionary history reveals that the IM24 Baramicin domain is not strictly useful in an immune context. We thus provide a case study for how an AMP-encoding gene might play dual roles in both immune and non-immune processes via its multiple peptide products. As many AMP genes encode polypeptides, a full understanding of how immune effectors interact with the nervous system will require consideration of all their peptide products.

Author summaryAntimicrobial peptides are immune proteins that directly combat infection, found across all animals. Antimicrobial peptides have long been implicated in neurological roles, though the ways these genes accomplish either immune or neurological function is poorly understood. One aspect of antimicrobial peptide genes that has received less attention is the fact that many genes encode multiple gene products on a precursor protein (including fruit fly Defensin, Attacin, Diptericin, Drosocin, or Baramicin). Here we show how the fruit fly Baramicin gene family has evolved for either immune-specific or neurological roles.One sub-peptide type (IM10-like) is repeatedly lost in genes lacking immune induction that are enriched in nerve tissue. In these nervous system-specific genes, a different sub-peptide is uniquely retained (IM24). This pattern has happened repeatedly across different species and gene lineages, suggesting the ancestral gene was equipped with specific sub-peptides adapted for either role. These findings suggest some antimicrobial peptide genes might accomplish alternative roles in immunity or neurology by different actions of their sub-peptides. It will be interesting to reflect on these findings in the light of inflammatory diseases, as many human neuropeptides and antimicrobial peptides have multiple mature products.