Enzyme

Bacteriophage

Nicotinamide adenine dinucleotide

Effector

Bacteria

Escherichia coli

Transcription factor

Biology

Microbiology

Phagemid

Gene

Bacillus subtilis

NAD+ kinase

DNA-binding protein

Cell biology

Genetics

Biochemistry

Nature Microbiology

Defence-associated sirtuins (DSRs) comprise a family of proteins that defend bacteria from phage infection via an unknown mechanism. These proteins are common in bacteria and harbour an N-terminal sirtuin (SIR2) domain. In this study we report that DSR proteins degrade nicotinamide adenine dinucleotide (NAD+) during infection, depleting the cell of this essential molecule and aborting phage propagation. Our data show that one of these proteins, DSR2, directly identifies phage tail tube proteins and then becomes an active NADase in Bacillus subtilis. Using a phage mating methodology that promotes genetic exchange between pairs of DSR2-sensitive and DSR2–resistant phages, we further show that some phages express anti-DSR2 proteins that bind and repress DSR2. Finally, we demonstrate that the SIR2 domain serves as an effector NADase in a diverse set of phage defence systems outside the DSR family. Our results establish the general role of SIR2 domains in bacterial immunity against phages. The SIR2-domain-containing protein DSR2 from Bacillus subtilis protects against SPR phage infection via NAD+ depletion. Some phages express anti-DSR2 proteins, blocking bacterial immunity.

Multiple phage resistance systems inhibit infection via SIR2-dependent NAD+ depletion