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

Yunxue Guo, Kaihao Tang, Brandon Sit, Jiayu Gu, Ran Chen, Xinqi Shao, Shituan Lin, Zixian Huang, Zhaolong Nie, Jianzhong Lin, Xiaoxiao Liu, Weiquan Wang, Xinyu Gao, Tianlang Liu, Fei Liu, Hongbo R. Luo, Matthew K. Waldor () and Xiaoxue Wang ()
Additional contact information
Yunxue Guo: Chinese Academy of Sciences
Kaihao Tang: Chinese Academy of Sciences
Brandon Sit: Harvard Medical School
Jiayu Gu: Chinese Academy of Sciences
Ran Chen: Chinese Academy of Sciences
Xinqi Shao: Chinese Academy of Medical Sciences and Peking Union Medical College
Shituan Lin: Chinese Academy of Sciences
Zixian Huang: Chinese Academy of Sciences
Zhaolong Nie: Chinese Academy of Sciences
Jianzhong Lin: Chinese Academy of Sciences
Xiaoxiao Liu: Chinese Academy of Sciences
Weiquan Wang: Chinese Academy of Sciences
Xinyu Gao: Chinese Academy of Sciences
Tianlang Liu: Chinese Academy of Sciences
Fei Liu: Chinese Academy of Medical Sciences and Peking Union Medical College
Hongbo R. Luo: Dana-Farber/Harvard Cancer Center
Matthew K. Waldor: Harvard Medical School
Xiaoxue Wang: Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51617-x

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