Bacterial ISG15-like systems function in anti-phage defense

Bacteria use a vast repertoire of defense systems to protect themselves against phage, i.e. viral, infection. Many of these systems were only recently discovered, revealing that several eukaryotic antiviral defense mechanisms such as the cGAS-STING pathway, viperin and gasdermin originated from bacteria. Here, we report a new bacterial anti-phage defense system containing a homolog of the eukaryotic ubiquitin-like protein ISG15 as well as homologs of dedicated E1 and E2 enzymes involved in the conjugation of ubiquitin-like proteins. We found this system to confer resistance against a broad range of phylogenetically distant phages. Furthermore, our data suggest that conjugation of the ISG15-like protein by the associated E1 and E2 enzymes is essential for the function of the system. ISG15-like defense systems are widespread in prokaryotes and were detected in hundreds of bacterial genomes.