RT Journal Article SR Electronic T1 Multiple phage resistance systems inhibit infection via SIR2-dependent NAD+ depletion JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.12.14.472415 DO 10.1101/2021.12.14.472415 A1 Garb, Jeremy A1 Lopatina, Anna A1 Bernheim, Aude A1 Zaremba, Mindaugas A1 Siksnys, Virginijus A1 Melamed, Sarah A1 Leavitt, Azita A1 Millman, Adi A1 Amitai, Gil A1 Sorek, Rotem YR 2021 UL http://biorxiv.org/content/early/2021/12/14/2021.12.14.472415.abstract AB Defense-associated sirtuins (DSR) comprise a family of proteins that defend bacteria from phage infection via an unknown mechanism. These proteins are common in bacteria and harbor 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 defense systems outside the DSR family. Our results establish the general role of SIR2 domains in bacterial immunity against phages.Competing Interest StatementR.S. is a scientific cofounder and advisor of BiomX and Ecophage. The other authors declare no competing interests.