Type III Druantia two-component antiphage defense depends on the DruH-DruE interaction for inhibiting viral DNA circularization and replication

Bacteria have evolved multiple immune systems to resist phage invasion, however, only a small part of the defensive mechanisms have been clearly uncovered. In this study, we report a type III Druantia two-component defense system, DruH-DruE, identified from Mycolicibacterium smegmatis . The DruH-DruE prevents phage DNA circularization and replication. DruE can be replaced from the defense system by either homolog in M. tuberculosis or M. smegmatis . The physical interaction between these two components is essential for fighting against phage infection. Mutations in the interaction sites led to the loss of phage-defending function of the system. The broad-spectrum antiphage ability of the defense system could be activated by the small tail protein Gp25 of phage A10ZJ24. This study fills a major gap in current knowledge of antiphage mechanism of type III Druantia defense system, expanding our understanding of the immune mechanisms in prokaryotic cells.