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Involvement of these extracellular organelles in intercellular communication and their implication in pathological conditions has fuelled intensive research on mammalian exosomes; however, currently, very little is known about exosomes in lower vertebrates. Here we show that, in primary cultures of head kidney leukocytes from Atlantic salmon (<jats:italic>Salmo salar<\/jats:italic>), phosphorothioate CpG oligodeoxynucleotides induce secretion of vesicles with characteristics very similar to these of mammalian exosomes. Further experiments revealed that the oligonucleotide\u2010induced exosome secretion did not depend on the CpG motifs but it relied on the phosphorothioate modification of the internucleotide linkage. Exosome secretion was also induced by genomic bacterial and eukaryotic <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> in toll\u2010like receptor 9\u2010negative piscine and human cell lines demonstrating that this is a phylogenetically conserved phenomenon which does not depend on activation of immune signaling pathways. In addition to exosomes, stimulation with phosphorothioate oligonucleotides and genomic <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> induced secretion of <jats:styled-content style=\"fixed-case\">LC<\/jats:styled-content>3B\u2010<jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>, an autophagosome marker, which was associated with vesicles of diverse size and morphology, possibly derived from autophagosome\u2010related intracellular compartments. Overall, this work reveals a previously unrecognized biological activity of phosphorothioate <jats:styled-content style=\"fixed-case\">ODN<\/jats:styled-content>s and genomic <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> \u2013 their capacity to induce secretion of exosomes and other types of extracellular vesicles. This finding might help shed light on the side effects of therapeutic phosphorothioate oligodeoxynucleotides and the biological activity of extracellular genomic <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> which is often upregulated in pathological conditions.<\/jats:p>","DOI":"10.1111\/febs.14601","type":"journal-article","created":{"date-parts":[[2018,6,28]],"date-time":"2018-06-28T20:25:50Z","timestamp":1530217550000},"page":"3114-3133","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Stimulation of exosome release by extracellular <scp>DNA<\/scp> is conserved across multiple cell types"],"prefix":"10.1111","volume":"285","author":[{"given":"Dimitar","family":"Iliev","sequence":"first","affiliation":[{"name":"Norwegian College of Fishery Science UiT The Arctic University of Norway Troms\u00f8 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