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

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 Bacillussubtilis protects against SPR phage infection via NAD(+) depletion. Some phages express anti-DSR2 proteins, blocking bacterial immunity.

Automated summary

DSR proteins defend bacteria from phage infection by degrading NAD(+) and acting as active NADases, with DSR2 directly identifying phage proteins. Some phages express anti-DSR2 proteins to block bacterial immunity. This study establishes the general role of SIR2 domains in bacterial immunity against phages.