Work

Periplasmic gatekeeping of phage DNA entry by an rSAM enzyme matured effector with HxS repeats

Year: 2026

Type: article

Abstract: In the relentless arms race between bacteria and phages, bacteria have evolved a variety of defense strategies to combat phage infection. However, no system has been previously demonstrated to specifically inhibit phage genomic DNA ejection. Here, we present a bacterial antiphage system, termed HXS, which provides broad-spectrum and robust antiphage activity by interfering with phage DNA entry. The HXS system consists of two radical S-adenosylmethionine (rSAM) enzymes (HxsB and HxsC), a small protein (HxsD), and the effector HxsA with a peptidoglycan-binding domain and five His-Xaa-Ser (HXS) repeats. HxsB/HxsC catalyze rSAM enzyme-dependent maturation of HxsA, including N-terminal processing and a site-specific +8 Da modification, thereby producing a periplasmic effector required for HXS defense. Biochemical evidence supports a model in which the matured effector likely engages incoming DNA electrostatically to arrest entry, establishing an rSAM enzyme-modified protein effector in antiphage defense. Here, the authors report a bacterial anti-phage defense system that targets the phage DNA entry phase. This system is termed HXS and consists of four proteins that function together to inhibit phage DNA entry providing broad-spectrum activity.

Source: Nature Communications

DOI: 10.1038/s41467-026-70567-0