Update ISG15-like
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Bacterial anti-phage systems are frequently clustered in microbial genomes, forming defense islands. This property enabled the recent discovery of multiple defense systems based on their genomic co-localization with known systems, but the full arsenal of anti-phage mechanisms remains unknown. We report the discovery of 21 defense systems that protect bacteria from phages, based on computational genomic analyses and phage-infection experiments. We identified multiple systems with domains involved in eukaryotic antiviral immunity, including those homologous to the ubiquitin-like ISG15 protein, dynamin-like domains, and SEFIR domains, and show their participation in bacterial defenses. Additional systems include domains predicted to manipulate DNA and RNA molecules, alongside toxin-antitoxin systems shown here to function in anti-phage defense. These systems are widely distributed in microbial genomes, and in some bacteria, they form a considerable fraction of the immune arsenal. Our data substantially expand the inventory of defense systems utilized by bacteria to counteract phage infection.
Multiple immune pathways in humans conjugate ubiquitin-like proteins to virus and host molecules as a means of antiviral defense. Here we studied an anti-phage defense system in bacteria, comprising a ubiquitin-like protein, ubiquitin-conjugating enzymes E1 and E2, and a deubiquitinase. We show that during phage infection, this system specifically conjugates the ubiquitin-like protein to the phage central tail fiber, a protein at the tip of the tail that is essential for tail assembly as well as for recognition of the target host receptor. Following infection, cells encoding this defense system release a mixture of partially assembled, tailless phage particles, and fully assembled phages in which the central tail fiber is obstructed by the covalently attached ubiquitin-like protein. These phages exhibit severely impaired infectivity, explaining how the defense system protects the bacterial population from the spread of phage infection. Our findings demonstrate that conjugation of ubiquitin-like proteins is an antiviral strategy conserved across the tree of life.
ISG15-like (Interferon-stimulated gene 15 - like) systems (also known as Bil systems for Bacterial ISG15-like systems) are a 4 gene defense system comprising a homolog of ubiquitin-like ISG15 (BilA), ubiquitin-conjugating enzymes E1 (BilD) and E2 (BilB), and a deubiquitinase (BilC) :ref{doi=10.1101/2023.09.04.556158,10.1016/j.chom.2022.09.017}. It has been shown to defend against muliple coliphages :ref{10.1016/j.chom.2022.09.017}. The Bil system is analogous to the ISG15 system in humans, that protects against virus.
Hör et al., have shown that the ISG15-like system defends bacteria against phages by impairing infectivity of newly synthezised phages. It does so by preventing tail assembly that leads to non-infective tailless phages or by producing modified tails with an obstructed tail tip that are not capable of infecting. More specifically, BilA is conjugated to the central tail fiber (CTF) protein of the phage :ref{doi=10.1101/2023.09.04.556158}.
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