Cytolethal distending toxins (CDTs) are tripartite eukaryotic genotoxins encoded in diverse bacterial and phage genomes. The cdtB subunit is a DNAse that causes eukaryotic cell cycle arrest and apoptosis, and in one context, is associated with resistance against parasitoid wasp infections. Here we report the discovery of functional cdtB copies in the nuclear genomes 5 of insect species from two distantly related insect orders, including fruit flies (Diptera: Drosophilidae) and aphids (Hemiptera: Aphididae). Insect cdtB copies are most closely related to bacteriophage copies, were horizontally transferred to insect genomes > 40 million years ago and encode a protein that retains ancestral DNase activity. This phage-derived toxin has been domesticated by diverse insects and we hypothesize that it is used as a defensive weapon against 10 parasitoid wasps. One Sentence Summary:We report horizontal transfer of the gene cytolethal distending toxin B, which encodes a DNase, into eukaryotic genomes from bacteriophage. 15 Significance: Cytolethal distending toxins (CDTs) are secreted by diverse pathogenic bacterial species to kill animal cells. The cdtB subunit enters cell nuclei, damaging the DNA and leading to mitotic arrest and apoptosis. In the pea aphid, a bacterial endosymbiont provides protection against wasp attack, possibly via cdtB. We discovered that this same endosymbiont-encoded lineage of cdtB was transferred to the genomes of Diptera and Hemiptera species and retains 20 ancestral DNase activity. This is the first report of cdtB outside of bacteria or phages. A toxin that first evolved to kill eukaryotic cells has been co-opted by insects, potentially to their benefit. 3 Main TextCytolethal distending toxins (CDTs) are widespread intracellular-acting eukaryotic genotoxins encoded by a gene family restricted to Actinobacteria, Proteobacteria and bacteriophage genomes (1). CDTs are found in diverse pathogens, including Campylobacter jejuni, Escherichia coli, Salmonella enterica, and Yersinia pestis and may be a cause of irritable bowel syndrome 5 (1). CDT holotoxin is an AB2 toxin typically encoded in a three-gene operon (cdtA, cdtB, and cdtC) (2) and cdtB is the catalytic subunit necessary for DNase activity (3, 4). CdtB nicking leads to DNA damage in eukaryotic cells followed by cell cycle arrest, cellular distention and death (5).Although cdtB is a eukaryotic genotoxin, in one context it is associated with increased 10 fitness of eukaryotes. Some strains of the bacterium Candidatus Hamiltonella defensa, a secondary endosymbiont of the pea aphid (Acyrthosiphon pisum), are infected with strains of the lysogenic bacteriophage APSE (6, 7). APSE-positive Ca. H defensa strains confer protection from attack by parasitoid braconid wasps that insert eggs into aphids (8). Comparative genomic studies point to cdtB, which is encoded in the genome of phage strain APSE-2, as a likely 15 candidate underlying this protective effect (6-8).We used a sequence similarity-based screen (9) to identify a cdtB homolog as a horizon...
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