Control of lysogeny and antiphage defense by a prophage-encoded kinase-phosphatase module

The filamentous 'Pf' bacteriophages of Pseudomonas aeruginosa play roles in biofilm formation and virulence, but mechanisms governing Pf prophage activation in biofilms are unclear. Here, we identify a prophage regulatory module, KKP (kinase-kinase-phosphatase), that controls virion production of co-resident Pf prophages and mediates host defense against diverse lytic phages. KKP consists of Ser/Thr kinases PfkA and PfkB, and phosphatase PfpC. The kinases have multiple host targets, one of which is MvaU, a host nucleoid-binding protein and known prophage-silencing factor. Characterization of KKP deletion and overexpression strains with transcriptional, protein-level and prophage-based approaches indicates that shifts in the balance between kinase and phosphatase activities regulate phage production by controlling MvaU phosphorylation. In addition, KKP acts as a tripartite toxin-antitoxin system that provides defense against some lytic phages. A conserved lytic phage replication protein inhibits the KKP phosphatase PfpC, stimulating toxic kinase activity and blocking lytic phage production. Thus, KKP represents a phosphorylation-based mechanism for prophage regulation and antiphage defense. The conservation of KKP gene clusters in >1000 diverse temperate prophages suggests that integrated control of temperate and lytic phage infection by KKP-like regulatory modules may play a widespread role in shaping host cell physiology.

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Publication Details

Journal
Nature Communications
Published
2024-08-23
DOI
https://doi.org/10.1038/s41467-024-51617-x
Citations
22
Primary Topic
Bacteriophages and microbial interactions
Type
article
Field-Weighted Citation Impact
10.10

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article

Control of lysogeny and antiphage defense by a prophage-encoded kinase-phosphatase module

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22 citations
Nature Communications
Bacteriophages and microbial interactions
10.10
article

Control of lysogeny and antiphage defense by a prophage-encoded kinase-phosphatase module

Shituan Lin, Brandon Sit, Tianlang Liu, Xinyu Gao, Matthew K. Waldor, Zhaolong Nie, Jianzhong Lin, Kaihao Tang, Jiayu Gu, Zixian Huang, Xinqi Shao, Yunxue Guo, Hongbo R. Luo, Xiaoxiao Liu, Ran Chen, Xiaoxue Wang, Weiquan Wang, Fei Liu
article en
22 citations

Abstract

The filamentous 'Pf' bacteriophages of Pseudomonas aeruginosa play roles in biofilm formation and virulence, but mechanisms governing Pf prophage activation in biofilms are unclear. Here, we identify a prophage regulatory module, KKP (kinase-kinase-phosphatase), that controls virion production of co-resident Pf prophages and mediates host defense against diverse lytic phages. KKP consists of Ser/Thr kinases PfkA and PfkB, and phosphatase PfpC. The kinases have multiple host targets, one of which is MvaU, a host nucleoid-binding protein and known prophage-silencing factor. Characterization of KKP deletion and overexpression strains with transcriptional, protein-level and prophage-based approaches indicates that shifts in the balance between kinase and phosphatase activities regulate phage production by controlling MvaU phosphorylation. In addition, KKP acts as a tripartite toxin-antitoxin system that provides defense against some lytic phages. A conserved lytic phage replication protein inhibits the KKP phosphatase PfpC, stimulating toxic kinase activity and blocking lytic phage production. Thus, KKP represents a phosphorylation-based mechanism for prophage regulation and antiphage defense. The conservation of KKP gene clusters in >1000 diverse temperate prophages suggests that integrated control of temperate and lytic phage infection by KKP-like regulatory modules may play a widespread role in shaping host cell physiology.

Nature CommunicationsVol. 15(1)
Brigham and Women's Hospital (US), Boston Children's Hospital (US), Howard Hughes Medical Institute (US), Harvard University (US), Chinese Academy of Sciences (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Institute of Oceanology (CN), South China Sea Institute Of Oceanology (CN), Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou) (CN), Dana-Farber/Harvard Cancer Center (US), Institute of Hematology & Blood Diseases Hospital (CN), University of Chinese Academy of Sciences (CN), Massachusetts Institute of Technology (US)
National Science Foundation, National Natural Science Foundation of China
Life in Land
Openalex Percentile: Top 1%
Bacteriophages and microbial interactions
10.10
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