An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp

Ahmad, Shehryar; Wang, Boyuan; Walker, Trent; Tran, Hiu-Ki R; Stogios, P.J.; Savchenko, Alexei; Grant, Robert A.; McArthur, Andrew G.; Laub, Michael T.; Whitney, John C.

doi:10.1038/s41586-019-1735-9

Cited by 118 publications

(140 citation statements)

References 40 publications

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“…One intriguing mystery is related to the an bacterial EATs and their lack of immunity genes in most cases. Nearly all an bacterial toxins produced by bacteria are accompanied by adjacent immunity genes 36,39,[55][56][57][58][59][60][61] , which we could not bioinforma cally iden fy next to most of the newly verified EAT genes. We do not know how these an bacterial EATs are being produced and loaded onto the eCIS system without killing the producer cell prior to eCIS release.…”

Section: Development Of a Comprehensive Ecis Databasementioning

confidence: 93%

The extracellular contractile injection system is enriched in environmental microbes and associates with numerous toxins

Geller

Pollin

Zlotkin

et al. 2020

Preprint

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Bacteria employ toxin delivery systems to exclude bacterial competitors and to infect host cells. Characterization of these systems and the toxins they secrete is important for understanding microbial interactions and virulence in different ecosystems. The extracellular Contractile Injection System (eCIS) is a toxin delivery particle that evolved from a bacteriophage tail. Four known eCIS systems have been shown to mediate interactions between bacteria and their invertebrate hosts, but the broad ecological function of these systems remains unknown. Here, we identify eCIS loci in 1,249 prokaryotic genomes and reveal a striking enrichment of these loci in environmental microbes and absence from mammalian pathogens. We uncovered 13 toxin genes that associate with eCIS from diverse microbes and show that they can inhibit growth of bacteria, yeast or both. We also found immunity genes that protect bacteria from self-intoxication, supporting an antibacterial role for eCIS. Furthermore, we identified multiple new eCIS core genes including a conserved eCIS transcriptional regulator. Finally, we present our data through eCIStem; an extensive eCIS repository. Our findings define eCIS as a widespread environmental prokaryotic toxin delivery system that likely mediates antagonistic interactions with eukaryotes and prokaryotes. Future understanding of eCIS functions can be leveraged for the development of new biological control systems, antimicrobials, and cell-free protein delivery tools.

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Section: Development Of a Comprehensive Ecis Databasementioning

confidence: 93%

The extracellular contractile injection system is enriched in environmental microbes and associates with numerous toxins

Geller

Pollin

Zlotkin

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…T6SSs use a bacteriophage-like mechanism to deliver effector proteins directly into target bacterial or eukaryotic cells (Basler et al, 2012;Hachani et al, 2016;Hood et al, 2010;Pukatzki et al, 2007). Antibacterial T6SS effectors disrupt diverse biological processes within target cells, and cognate immunity proteins protect T6SS-producing cells from autotoxicity (Ahmad et al, 2019;Russell et al, 2014;Ting et al, 2018). Type VI secretion (T6S) has been studied in the Bcc pathogen Burkholderia cenocepacia strain J2315 (BcJ2315), which produces a T6SS that is important for infection of macrophages and influences the immune response to this pathogen (Aubert et al, 2015;Hunt et al, 2004;Rosales-Reyes et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Host Adaptation Predisposes Pseudomonas aeruginosa to Type VI Secretion System-Mediated Predation by the Burkholderia cepacia Complex

Perault

Chandler

Rasko

et al. 2020

Preprint

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Pseudomonas aeruginosa (Pa) and Burkholderia cepacia complex (Bcc) species are opportunistic lung pathogens of individuals with cystic fibrosis (CF). While Pa can initiate longterm infections in younger CF patients, Bcc infections only arise in teenagers and adults. Both Pa and Bcc use type VI secretion systems (T6SS) to mediate interbacterial competition. Here, we show that Pa isolates from teenage/adult CF patients, but not those from young CF patients, are outcompeted by the epidemic Bcc isolate Burkholderia cenocepacia strain AU1054 (BcAU1054) in a T6SS-dependent manner. The genomes of susceptible Pa isolates harbor T6SS-abrogating mutations, the repair of which, in some cases, rendered the isolates resistant.Moreover, seven of eight Bcc strains outcompeted Pa strains isolated from the same patients.Our findings suggest that certain mutations that arise as Pa adapts to the CF lung abrogate T6SS activity, making Pa and its human host susceptible to potentially fatal Bcc superinfection.

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“…Antibacterial effectors delivered by the T6SS induce toxicity by targeting important structural components or affecting target-cell metabolism. Several families of effectors have been described, including peptidoglycan amidases and hydrolases, phospholipases, nucleases, NAD(P) + -glycohydrolases, pore forming proteins and enzymes that synthesize (p)ppApp (Russell et al, 2012; Koskiniemi et al, 2013; Whitney et al, 2013; Ma et al, 2014; Tang et al, 2018; Ahmad et al, 2019; Jana et al, 2019; Mariano et al, 2019; Wood et al, 2019). An example of an effector inducing toxicity by posttranslational modification (ADP-ribosylation) of the cytoskeleton component FtsZ has also been reported (Ting et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

A Superfamily of T6SS Antibacterial Effectors Displaying L,D-carboxypeptidase Activity Towards Peptidoglycan

Sibinelli-Sousa

Hespanhol

Nicastro

et al. 2020

Preprint

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SummaryType VI secretion systems (T6SSs) are contractile nanomachines used by bacteria to inject toxic effectors into competitors. The identity and mechanism of many effectors remain unknown. We characterized a Salmonella SPI-6 T6SS antibacterial effector called Tae5STM (type VI amidase effector 5). Tae5STM is toxic in target-cell periplasm and is neutralized by its cognate immunity protein (Tai5STM). Microscopy analysis revealed that cells expressing the effector stop dividing and lose cell envelope integrity. Bioinformatic analysis uncovered similarities between Tae5STM and the catalytic domain of L,D-transpeptidase. Point mutations on conserved catalytic histidine and cysteine residues abrogated toxicity. Biochemical assays revealed that Tae5STM displays L,D-carboxypeptidase activity, cleaving peptidoglycan tetrapeptides between meso-diaminopimelic acid3 and D-alanine4. Phylogenetic analysis showed that Tae5STM homologs constitutes a new superfamily of T6SS-associated amidase effectors distributed among α-, β- and γ-proteobacteria. This work expands our current knowledge about bacterial effectors used in interbacterial competition.

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An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp

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Cited by 118 publications

References 40 publications

The extracellular contractile injection system is enriched in environmental microbes and associates with numerous toxins

The extracellular contractile injection system is enriched in environmental microbes and associates with numerous toxins

Host Adaptation Predisposes Pseudomonas aeruginosa to Type VI Secretion System-Mediated Predation by the Burkholderia cepacia Complex

A Superfamily of T6SS Antibacterial Effectors Displaying L,D-carboxypeptidase Activity Towards Peptidoglycan

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