Multiple Phage Resistance Systems Inhibit Infection Via SIR2-dependent NAD Depletion

Overview

Journal Nat Microbiol

Specialties Microbiology
Parasitology

Date 2022 Oct 3

PMID 36192536

Authors

Jeremy Garb

Anna Lopatina

Aude Bernheim

Mindaugas Zaremba

Virginijus Siksnys

Sarah Melamed

Azita Leavitt

Adi Millman

Gil Amitai

Rotem Sorek

Affiliations

Soon will be listed here.

Abstract

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.

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References

North B, Verdin E . Sirtuins: Sir2-related NAD-dependent protein deacetylases. Genome Biol. 2004; 5(5):224. PMC: 416462. DOI: 10.1186/gb-2004-5-5-224. View

Imai S, ARMSTRONG C, Kaeberlein M, Guarente L . Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000; 403(6771):795-800. DOI: 10.1038/35001622. View

Tanny J, Dowd G, Huang J, Hilz H, Moazed D . An enzymatic activity in the yeast Sir2 protein that is essential for gene silencing. Cell. 2000; 99(7):735-45. DOI: 10.1016/s0092-8674(00)81671-2. View

Dang W . The controversial world of sirtuins. Drug Discov Today Technol. 2014; 12:e9-e17. PMC: 4101544. DOI: 10.1016/j.ddtec.2012.08.003. View

Makarova K, Wolf Y, van der Oost J, Koonin E . Prokaryotic homologs of Argonaute proteins are predicted to function as key components of a novel system of defense against mobile genetic elements. Biol Direct. 2009; 4:29. PMC: 2743648. DOI: 10.1186/1745-6150-4-29. View

Doron S, Melamed S, Ofir G, Leavitt A, Lopatina A, Keren M . Systematic discovery of antiphage defense systems in the microbial pangenome. Science. 2018; 359(6379). PMC: 6387622. DOI: 10.1126/science.aar4120. View

Ofir G, Herbst E, Baroz M, Cohen D, Millman A, Doron S . Antiviral activity of bacterial TIR domains via immune signalling molecules. Nature. 2021; 600(7887):116-120. DOI: 10.1038/s41586-021-04098-7. View

Gao L, Altae-Tran H, Bohning F, Makarova K, Segel M, Schmid-Burgk J . Diverse enzymatic activities mediate antiviral immunity in prokaryotes. Science. 2020; 369(6507):1077-1084. PMC: 7985843. DOI: 10.1126/science.aba0372. View

Lopatina A, Tal N, Sorek R . Abortive Infection: Bacterial Suicide as an Antiviral Immune Strategy. Annu Rev Virol. 2020; 7(1):371-384. DOI: 10.1146/annurev-virology-011620-040628. View

10.

Kohm K, Hertel R . The life cycle of SPβ and related phages. Arch Virol. 2021; 166(8):2119-2130. PMC: 8270828. DOI: 10.1007/s00705-021-05116-9. View

11.

Noyer-Weidner M, Jentsch S, Pawlek B, Gunthert U, Trautner T . Restriction and modification in Bacillus subtilis: DNA methylation potential of the related bacteriophages Z, SPR, SP beta, phi 3T, and rho 11. J Virol. 1983; 46(2):446-53. PMC: 255146. DOI: 10.1128/JVI.46.2.446-453.1983. View

12.

Dragos A, Priyadarshini B, Hasan Z, Strube M, Kempen P, Maroti G . Pervasive prophage recombination occurs during evolution of spore-forming Bacilli. ISME J. 2020; 15(5):1344-1358. PMC: 8115142. DOI: 10.1038/s41396-020-00854-1. View

13.

Bernheim A, Millman A, Ofir G, Meitav G, Avraham C, Shomar H . Prokaryotic viperins produce diverse antiviral molecules. Nature. 2020; 589(7840):120-124. PMC: 7610908. DOI: 10.1038/s41586-020-2762-2. View

14.

Freire D, Gutierrez C, Garza-Garcia A, Grabowska A, Sala A, Ariyachaokun K . An NAD Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death. Mol Cell. 2019; 73(6):1282-1291.e8. PMC: 6436930. DOI: 10.1016/j.molcel.2019.01.028. View

15.

Morehouse B, Govande A, Millman A, Keszei A, Lowey B, Ofir G . STING cyclic dinucleotide sensing originated in bacteria. Nature. 2020; 586(7829):429-433. PMC: 7572726. DOI: 10.1038/s41586-020-2719-5. View

16.

Skjerning R, Senissar M, Winther K, Gerdes K, Brodersen D . The RES domain toxins of RES-Xre toxin-antitoxin modules induce cell stasis by degrading NAD+. Mol Microbiol. 2018; 111(1):221-236. DOI: 10.1111/mmi.14150. View

17.

Tang J, Bullen N, Ahmad S, Whitney J . Diverse NADase effector families mediate interbacterial antagonism via the type VI secretion system. J Biol Chem. 2017; 293(5):1504-1514. PMC: 5798281. DOI: 10.1074/jbc.RA117.000178. View

18.

Tal N, Morehouse B, Millman A, Stokar-Avihail A, Avraham C, Fedorenko T . Cyclic CMP and cyclic UMP mediate bacterial immunity against phages. Cell. 2021; 184(23):5728-5739.e16. PMC: 9070634. DOI: 10.1016/j.cell.2021.09.031. View

19.

Millman A, Bernheim A, Stokar-Avihail A, Fedorenko T, Voichek M, Leavitt A . Bacterial Retrons Function In Anti-Phage Defense. Cell. 2020; 183(6):1551-1561.e12. DOI: 10.1016/j.cell.2020.09.065. View

20.

Kaufmann G . Anticodon nucleases. Trends Biochem Sci. 2000; 25(2):70-4. DOI: 10.1016/s0968-0004(99)01525-x. View