New progress has been made in the participation of bacterial toxin-antitoxin system in the regulation of bacteriophage life cycle

Recently, Cell Reports published a research paper by the protein science research team of the State Key Laboratory of Agricultural Microbiology of Huazhong Agricultural University and Hubei Hongshan Laboratory online, entitled "Bacterial MazF/MazE toxin-antitoxin suppresses lytic propagation of arbitrium-containing phages".
This study elucidates a novel regulatory mechanism
for lysogen-determined phage cleavage.

Bacteriophages are the most abundant organisms
on Earth.
40~50% of the bacterial genome carries bacteriophage DNA, which exists
in the form of lysogens.
Phage lysogen conversion can change the phenotype and physiological characteristics of host bacteria, affecting bacterial metabolism, virulence, and antibiotic resistance
.

In recent years, information exchange systems similar to bacterial quorum sensing have been identified in bacteriophages to regulate their life cycle
.
After the phage infects the host cell, it secretes a signal short peptide to the extracellular, and when the short peptide accumulates to a certain concentration, it enters the cell and binds to the receptor, promoting the transition
of the phage from lysis to lysogen.
This is the first signaling communication system to be found in viruses, called the "arbitrium" system, which is widespread in Bacillus bacteriophages or bacterial mobile elements
.
However, how the signaling short peptide binds to the receptor plays a role in phage lysogen determination, and the downstream signaling pathway and molecular mechanism are unclear
.

Figure Signaling short peptides regulate phage lysogen-determined signaling pathways

The authors identified by RNA-seq that signal short peptides promote the expression of a downstream gene cluster during bacteriophage infection with bacteria, and further determined that yopM genes inhibit the cleavage cycle of bacteriophages, and yopR genes promote the occurrence of lysogens
.
Combined with mass spectrometry analysis, it was found that the bacteriophage YopM protein can target the host bacterial toxin-antitoxin MazEF system, and promote the degradation
of RNA by toxin MazF nuclease by competitively binding to antitoxin MazE.
The authors demonstrated that under the action of signal short peptides, bacterial MazEF complexes cause abortive infection of bacteriophages, cause bacterial death, inhibit phage lysis pathways, and this mechanism is conserved in SPbeta-like phages
.
The above results identify the key genes of phage signaling molecules that regulate their life cycle, and are also the first to find that bacteriophage proteins can activate the toxin-antitoxin system of bacteria, providing new insights
for understanding bacteria-phage coexistence and evolution.

Focusing on "phage-host interaction and signal regulation", the research group studied the working model of signal short peptide regulating phage life cycle (Nature Microbiology, 2018; Cell Discovery, 2019) and the molecular mechanism of bacterial resistance to phage infection (Nature Microbiology, 2022).

This work elucidates the signaling pathway by which signal short peptides regulate phage lysogen-determination, which is another breakthrough
in focusing phage signal communication system.