Insertion sequence transposition activates antimycobacteriophage immunity through an lsr2‐silenced lipid metabolism gene island

• Published in: mLife Vol. 3; no. 1; pp. 87 - 100
• Main Authors: Li, Yakun, Wei, Yuyun, Guo, Xiao, Li, Xiaohui, Lu, Lining, Hu, Lihua, He, Zheng‐Guo
• Format: Journal Article
• Language: English
• Published: Australia John Wiley & Sons, Inc 01.03.2024; John Wiley and Sons Inc; Wiley
• Subjects: Adsorption; antiphage defense; Bacteria; bacteriophage; CRISPR; Defense; gene island; Genes; Genomes; Genotype & phenotype; Infections; insertion sequence; Metabolism; Mutation; mycobacteria; Original Research; Proteins; Tuberculosis; insertion sequence; bacteriophage; mycobacteria; antiphage defense; gene island
• ISSN: 2770-100X; 2097-1699; 2770-100X
• DOI: 10.1002/mlf2.12106

Insertion sequences (ISs) exist widely in bacterial genomes, but their roles in the evolution of bacterial antiphage defense remain to be clarified. Here, we report that, under the pressure of phage infection, the IS1096 transposition of Mycobacterium smegmatis into the lsr2 gene can occur at high frequencies, which endows the mutant mycobacterium with a broad‐spectrum antiphage ability. Lsr2 functions as a negative regulator and directly silences expression of a gene island composed of 11 lipid metabolism‐related genes. The complete or partial loss of the gene island leads to a significant decrease of bacteriophage adsorption to the mycobacterium, thus defending against phage infection. Strikingly, a phage that has evolved mutations in two tail‐filament genes can re‐escape from the lsr2 inactivation‐triggered host defense. This study uncovered a new signaling pathway for activating antimycobacteriophage immunity by IS transposition and provided insight into the natural evolution of bacterial antiphage defense. Impact statement Very few antiphage mechanisms have been clearly characterized in mycobacterial species, although these bacterial genomes encode potential adaptive and innate immune systems. In this study, we show that endogenous insertion sequences in mycobacteria can activate the defensive gene islands, thereby helping bacteria quickly acquire a broad‐spectrum antiphage ability in a short period of time. This may represent a new acquired defense strategy different from the previously reported CRISPR antiphage mechanism.