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New players in the toxin field: polymorphic toxin systems in bacteria.

ABSTRACT: Bacteria have evolved numerous strategies to increase their competitiveness and fight against each other. Indeed, a large arsenal of antibacterial weapons is available in order to inhibit the proliferation of competitor cells. Polymorphic toxin systems (PTS), recently identified by bioinformatics in all major bacterial lineages, correspond to such a system primarily involved in conflict between related bacterial strains. They are typically composed of a secreted multidomain toxin, a protective immunity protein, and multiple cassettes encoding alternative toxic domains. The C-terminal domains of polymorphic toxins carry the toxic activity, whereas the N-terminal domains are related to the trafficking mode. In silico analysis of PTS identified over 150 distinct toxin domains, including putative nuclease, deaminase, or peptidase domains. Immunity genes found immediately downstream of the toxin genes encode small proteins that protect bacteria against their own toxins or against toxins secreted by neighboring cells. PTS encompass well-known colicins and pyocins, contact-dependent growth inhibition systems which include CdiA and Rhs toxins and some effectors of type VI secretion systems. We have recently characterized the MafB toxins, a new family of PTS deployed by pathogenic Neisseria spp. Many other putative PTS have been identified by in silico predictions but have yet to be characterized experimentally. However, the high number of these systems suggests that PTS have a fundamental role in bacterial biology that is likely to extend beyond interbacterial competition.

SUBMITTER: Jamet A

PROVIDER: S-EPMC4436062 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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New players in the toxin field: polymorphic toxin systems in bacteria.

Jamet Anne A Nassif Xavier X

mBio 20150505 3

Bacteria have evolved numerous strategies to increase their competitiveness and fight against each other. Indeed, a large arsenal of antibacterial weapons is available in order to inhibit the proliferation of competitor cells. Polymorphic toxin systems (PTS), recently identified by bioinformatics in all major bacterial lineages, correspond to such a system primarily involved in conflict between related bacterial strains. They are typically composed of a secreted multidomain toxin, a protective i ...[more]

PMID: 25944858

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Project description:Bacteria have developed several molecular conflict systems to facilitate kin recognition and non-kin competition to gain advantages in the acquisition of growth niches and of limited resources. One such example is a large class of so-called polymorphic toxin systems (PTSs), which comprise a variety of the toxin proteins secreted via T2SS, T5SS, T6SS, T7SS and many others. These systems are highly divergent in terms of sequence/structure, domain architecture, toxin-immunity association, and organization of the toxin loci, which makes it difficult to identify and characterize novel systems using traditional experimental and bioinformatic strategies. In recent years, we have been developing and utilizing unique genome-mining strategies and pipelines, based on the organizational principles of both domain architectures and genomic loci of PTSs, for an effective and comprehensive discovery of novel PTSs, dissection of their components, and prediction of their structures and functions. In this study, we present our systematic discovery of a new type of PTS (S8-PTS) in several gram-positive bacteria. We show that the S8-PTS contains three components: a peptidase of the S8 family (subtilases), a polymorphic toxin, and an immunity protein. We delineated the typical organization of these polymorphic toxins, in which a N-terminal signal peptide is followed by a potential receptor binding domain, BetaH, and one of 16 toxin domains. We classified each toxin domain by the distinct superfamily to which it belongs, identifying nine BECR ribonucleases, one Restriction Endonuclease, one HNH nuclease, two novel toxin domains homologous to the VOC enzymes, one toxin domain with the Frataxin-like fold, and several other unique toxin families such as Ntox33 and HicA. Accordingly, we identified 20 immunity families and classified them into different classes of folds. Further, we show that the S8-PTS-associated peptidases are analogous to many other processing peptidases found in T5SS, T7SS, T9SS, and many proprotein-processing peptidases, indicating that they function to release the toxin domains during secretion. The S8-PTSs are mostly found in animal and plant-associated bacteria, including many pathogens. We propose S8-PTSs will facilitate the competition of these bacteria with other microbes or contribute to the pathogen-host interactions.

Project description:Proteinaceous toxins are observed across all levels of inter-organismal and intra-genomic conflicts. These include recently discovered prokaryotic polymorphic toxin systems implicated in intra-specific conflicts. They are characterized by a remarkable diversity of C-terminal toxin domains generated by recombination with standalone toxin-coding cassettes. Prior analysis revealed a striking diversity of nuclease and deaminase domains among the toxin modules. We systematically investigated polymorphic toxin systems using comparative genomics, sequence and structure analysis.Polymorphic toxin systems are distributed across all major bacterial lineages and are delivered by at least eight distinct secretory systems. In addition to type-II, these include type-V, VI, VII (ESX), and the poorly characterized "Photorhabdus virulence cassettes (PVC)", PrsW-dependent and MuF phage-capsid-like systems. We present evidence that trafficking of these toxins is often accompanied by autoproteolytic processing catalyzed by HINT, ZU5, PrsW, caspase-like, papain-like, and a novel metallopeptidase associated with the PVC system. We identified over 150 distinct toxin domains in these systems. These span an extraordinary catalytic spectrum to include 23 distinct clades of peptidases, numerous previously unrecognized versions of nucleases and deaminases, ADP-ribosyltransferases, ADP ribosyl cyclases, RelA/SpoT-like nucleotidyltransferases, glycosyltranferases and other enzymes predicted to modify lipids and carbohydrates, and a pore-forming toxin domain. Several of these toxin domains are shared with host-directed effectors of pathogenic bacteria. Over 90 families of immunity proteins might neutralize anywhere between a single to at least 27 distinct types of toxin domains. In some organisms multiple tandem immunity genes or immunity protein domains are organized into polyimmunity loci or polyimmunity proteins. Gene-neighborhood-analysis of polymorphic toxin systems predicts the presence of novel trafficking-related components, and also the organizational logic that allows toxin diversification through recombination. Domain architecture and protein-length analysis revealed that these toxins might be deployed as secreted factors, through directed injection, or via inter-cellular contact facilitated by filamentous structures formed by RHS/YD, filamentous hemagglutinin and other repeats. Phyletic pattern and life-style analysis indicate that polymorphic toxins and polyimmunity loci participate in cooperative behavior and facultative 'cheating' in several ecosystems such as the human oral cavity and soil. Multiple domains from these systems have also been repeatedly transferred to eukaryotes and their viruses, such as the nucleo-cytoplasmic large DNA viruses.Along with a comprehensive inventory of toxins and immunity proteins, we present several testable predictions regarding active sites and catalytic mechanisms of toxins, their processing and trafficking and their role in intra-specific and inter-specific interactions between bacteria. These systems provide insights regarding the emergence of key systems at different points in eukaryotic evolution, such as ADP ribosylation, interaction of myosin VI with cargo proteins, mediation of apoptosis, hyphal heteroincompatibility, hedgehog signaling, arthropod toxins, cell-cell interaction molecules like teneurins and different signaling messengers.

Dataset Information

New players in the toxin field: polymorphic toxin systems in bacteria.

Publications

New players in the toxin field: polymorphic toxin systems in bacteria.

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