Bacterial retrons encode phage-defending tripartite toxin–antitoxin systems

Bobonis, Jacob; Mitosch, Karin; Mateus, André; Karcher, Nicolai; Kritikos, George; Selkrig, Joel; Zietek, Matylda; Monzon, Vivian; Pfalz, Birgit; García-Santamarina, Sarela; Galardini, Marco; Sueki, Anna; Kobayashi, Callie; Stein, Frank; Bateman, Alex; Zeller, Georg; Savitski, Mikhail M.; Elfenbein, Johanna R.; Andrews‐Polymenis, Helene; Typas, Athanasios

doi:10.1038/s41586-022-05091-4

Cited by 97 publications

(70 citation statements)

References 85 publications

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“…A common theme among retron-interacting proteins found in this and other studies, including T7 SSB, T5 A1, Rac prophage DNA exonuclease, E. coli DNA methylase (Bobonis et al, 2022) and RecBCD, is that they all have the capacity or predicted capacity to interact with DNA. It is possible that interaction of these proteins with the retrongenerated ssDNA forms part of the basis for their sensing by the retron system.…”

Section: Phage Triggers For Retron Defense Systemssupporting

confidence: 54%

“…The retron RT reverse transcribes the non-coding RNA to form a chimeric RNA-DNA molecule which, together with the RT, has been hypothesized to sense phage infection. Defense by retrons involves cell suicide or growth arrest in response to phage infection (abortive infection), which is carried out by the associated effector protein (Bobonis et al, 2022; Millman et al, 2020). Based on phage escaper data, it was previously shown that retron Ec48 “guards” the cellular RecBCD complex, such that when phages inhibit RecBCD, the retron becomes active and leads the cell to growth arrest (Millman et al, 2020).…”

Section: Resultsmentioning

confidence: 99%

“…Based on phage escaper data, it was previously shown that retron Ec48 “guards” the cellular RecBCD complex, such that when phages inhibit RecBCD, the retron becomes active and leads the cell to growth arrest (Millman et al, 2020). Studies on another retron, St85, demonstrated that phage proteins that degrade or modify the retron reverse-transcribed DNA activate the toxicity of the retron effector (Bobonis et al, 2022). However, it is unknown how other retrons sense phages.…”

Section: Resultsmentioning

confidence: 99%

“…Selected retrons from the tree are marked, with the predicted phage-encoded activator denoted. The triggering mechanism for the St85 retron is reported based on a previous study (Bobonis et al, 2022). (D) Expression of a phage-encoded ssDNA binding protein (SSB) activates toxicity in a strain that contains the retron Eco8 system.…”

Section: Phage Triggers For Retron Defense Systemsmentioning

confidence: 99%

“…However, studies over the past few years have revealed a plethora of additional defense mechanisms commonly employed by bacteria. These include phage restriction by prokaryotic Argonaute proteins (Garb et al, 2021; Koopal et al, 2022; Kuzmenko et al, 2020; Zaremba et al, 2021), production of small molecules that block phage propagation (Bernheim et al, 2021; Kever et al, 2022; Kronheim et al, 2018), depletion of molecules essential for phage replication (Garb et al, 2021; Hsueh et al, 2022; Ofir et al, 2021; Tal et al, 2022), systems that use small molecule signaling to activate immune effectors (Cohen et al, 2019; Ofir et al, 2021; Tal et al, 2021; Whiteley et al, 2019), retrons that involve reverse transcription of non-coding RNAs (Bobonis et al, 2022; Gao et al, 2020; Millman et al, 2020), and more (Doron et al, 2018; Gao et al, 2020; Goldfarb et al, 2015; Johnson et al, 2022; Millman et al, 2022; Ofir et al, 2018; Rousset et al, 2022; Vassallo et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

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Discovery of phage determinants that confer sensitivity to bacterial immune systems

Stokar-Avihail

Fedorenko

Garb

et al. 2022

Preprint

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Over the past few years, numerous anti-phage defense systems have been discovered in bacteria. While the mechanism of defense for some of these systems is understood, a major unanswered question is how these systems sense phage infection. To systematically address this question, we isolated 192 phage mutants that escape 19 different defense systems. In many cases, these escaper phages were mutated in the gene sensed by the defense system, enabling us to map the phage determinants that confer sensitivity to bacterial immunity. Our data identify specificity determinants of diverse retron systems and reveal phage-encoded triggers for multiple abortive infection systems. We find general themes in phage sensing and demonstrate that mechanistically diverse systems have converged to sense either the core replication machinery of the phage, phage structural components, or host takeover mechanisms. Combining our data with previous findings, we formulate key principles on how bacterial immune systems sense phage invaders.

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Section: Phage Triggers For Retron Defense Systemssupporting

confidence: 54%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Phage Triggers For Retron Defense Systemsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Discovery of phage determinants that confer sensitivity to bacterial immune systems

Stokar-Avihail

Fedorenko

Garb

et al. 2022

Preprint

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The immune system of prokaryotes: potential applications and implications for gene editing

Liu,

Wang

et al. 2024

Biotechnology Journal

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Gene therapy has revolutionized the treatment of genetic diseases. Spearheading this revolution are sophisticated genome editing methods such as TALENs, ZFNs, and CRISPR‐Cas, which trace their origins back to prokaryotic immune systems. Prokaryotes have developed various antiviral defense systems to combat viral attacks and the invasion of genetic elements. The comprehension of these defense mechanisms has paved the way for the development of indispensable tools in molecular biology. Among them, restriction endonuclease originates from the innate immune system of bacteria. The CRISPR‐Cas system, a widely applied genome editing technology, is derived from the prokaryotic adaptive immune system. Single‐base editing is a precise editing tool based on CRISPR‐Cas system that involves deamination of target base. It is worth noting that prokaryotes possess deamination enzymes as part of their defense arsenal over foreign genetic material. Furthermore, prokaryotic Argonauts (pAgo) proteins, also function in anti‐phage defense, play an important role in complementing the CRISPR‐Cas system by addressing certain limitations it may have. Recent studies have also shed light on the significance of Retron, a reverse transcription transposon previously showed potential in genome editing, has also come to light in the realm of prokaryotic immunity. These noteworthy findings highlight the importance of studying prokaryotic immune system for advancing genome editing techniques. Here, both the origin of prokaryotic immunity underlying aforementioned genome editing tools, and potential applications of deaminase, pAgo protein and reverse transcriptase in genome editing among prokaryotes were introduced, thus emphasizing the fundamental mechanism and significance of prokaryotic immunity.

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Overcoming Bacteriophage Contamination in Bioprocessing: Strategies and Applications

Zou,

Mo,

Wang

et al. 2024

Small Methods

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Bacteriophage contamination has a devastating impact on the viability of bacterial hosts and can significantly reduce the productivity of bioprocesses in biotechnological industries. The consequences range from widespread fermentation failure to substantial economic losses, highlighting the urgent need for effective countermeasures. Conventional prevention methods, which focus primarily on the physical removal of bacteriophages from equipment, bioprocess units, and the environment, have proven ineffective in preventing phage entry and contamination. The coevolutionary dynamics between phages and their bacterial hosts have spurred the development of a diverse repertoire of antiviral defense mechanisms within microbial communities. These naturally occurring defense strategies can be harnessed through genetic engineering to convert phage‐sensitive hosts into robust, phage‐resistant cell factories, providing a strategic approach to mitigate the threats posed by bacteriophages to industrial bacterial processes. In this review, an overview of the various defense strategies and immune systems that curb the propagation of bacteriophages and highlight their applications in fermentation bioprocesses to combat phage contamination is provided. Additionally, the tactics employed by phages to circumvent these defense strategies are also discussed, as preventing the emergence of phage escape mutants is a key component of effective contamination management.

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Bacterial retrons encode phage-defending tripartite toxin–antitoxin systems

Cited by 97 publications

References 85 publications

Discovery of phage determinants that confer sensitivity to bacterial immune systems

Discovery of phage determinants that confer sensitivity to bacterial immune systems

The immune system of prokaryotes: potential applications and implications for gene editing

Overcoming Bacteriophage Contamination in Bioprocessing: Strategies and Applications

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