Mechanism of Tc toxin action revealed in molecular detail

Meusch, D.; Gatsogiannis, Christos; Efremov, Rouslan G.; Lang, Alexander E.; Hofnagel, Oliver; Vetter, Ingrid R.; Aktories, Klaus; Raunser, Stefan

doi:10.1038/nature13015

Cited by 154 publications

(274 citation statements)

References 65 publications

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“…These genes included several toxin complex (Tc) gene clusters (Fig. 2C), which have been associated with both host specificity and pathogenesis (44). One of these loci, on contig NODE28, was found to contain two chitinase genes.…”

Section: Photorhabdus/ Xenorhabdusmentioning

confidence: 99%

Lack of Overt Genome Reduction in the Bryostatin-Producing Bryozoan Symbiont “Candidatus Endobugula sertula”

Miller

Vanee

Fong

et al. 2016

Appl Environ Microbiol

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The uncultured bacterial symbiont "Candidatus Endobugula sertula" is known to produce cytotoxic compounds called bryostatins, which protect the larvae of its host, Bugula neritina. The symbiont has never been successfully cultured, and it was thought that its genome might be significantly reduced. Here, we took a shotgun metagenomics and metatranscriptomics approach to assemble and characterize the genome of "Ca. Endobugula sertula." We found that it had specific metabolic deficiencies in the biosynthesis of certain amino acids but few other signs of genome degradation, such as small size, abundant pseudogenes, and low coding density. We also identified homologs to genes associated with insect pathogenesis in other gammaproteobacteria, and these genes may be involved in host-symbiont interactions and vertical transmission. Metatranscriptomics revealed that these genes were highly expressed in a reproductive host, along with bry genes for the biosynthesis of bryostatins. We identified two new putative bry genes fragmented from the main bry operon, accounting for previously missing enzymatic functions in the pathway. We also determined that a gene previously assigned to the pathway, bryS, is not expressed in reproductive tissue, suggesting that it is not involved in the production of bryostatins. Our findings suggest that "Ca. Endobugula sertula" may be able to live outside the host if its metabolic deficiencies are alleviated by medium components, which is consistent with recent findings that it may be possible for "Ca. Endobugula sertula" to be transmitted horizontally. IMPORTANCEThe bryostatins are potent protein kinase C activators that have been evaluated in clinical trials for a number of indications, including cancer and Alzheimer's disease. There is, therefore, considerable interest in securing a renewable supply of these compounds, which is currently only possible through aquaculture of Bugula neritina and total chemical synthesis. However, these approaches are labor-intensive and low-yielding and thus preclude the use of bryostatins as a viable therapeutic agent. Our genome assembly and transcriptome analysis for "Ca. Endobugula sertula" shed light on the metabolism of this symbiont, potentially aiding isolation and culturing efforts. Our identification of additional bry genes may also facilitate efforts to express the complete pathway heterologously. Marine invertebrates, such as tunicates and sponges, are known to harbor symbiotic communities of bacteria. Because these animals are sessile and have limited physical defenses, their microbiomes are thought to serve defensive functions, and bacterial symbionts in these invertebrates have been implicated in the production of many bioactive small molecules (1, 2). Such small molecules can possess therapeutically relevant activities, so there is great interest in studying the biosynthetic potential and symbiotic functions of these defensive microorganisms (1, 2). However, most symbionts (and most environmental bacteria in general [1,3,4]) are difficul...

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Section: Photorhabdus/ Xenorhabdusmentioning

confidence: 99%

Lack of Overt Genome Reduction in the Bryostatin-Producing Bryozoan Symbiont “Candidatus Endobugula sertula”

Miller

Vanee

Fong

et al. 2016

Appl Environ Microbiol

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“…Sequence analyses using HHpred (43) and Phyre2 (44,45) show that the ORF2402 carries a putative colicin domain (HHpred probability 21% and Phyre2 confidence 78%) and that the ORF0928 carries a TC toxin domain (HHpred probability 100% and Phyre2 confidence 100%). The TC toxin complexes are important virulence factors in many bacterial pathogens, including Photorhabdus luminescens and Yersinia pestis, which target insects and mammalian cells (46,47). We thus named ORF2402 TseC for its colicin domain and ORF0928 TseI for its potential insecticidal activity.…”

Section: Vc1417 Belongs To a Large Family Of Proteins With A Conservedmentioning

confidence: 99%

Identification of divergent type VI secretion effectors using a conserved chaperone domain

Liang

Moore

Wilton

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

146

186

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The type VI secretion system (T6SS) is a lethal weapon used by many bacteria to kill eukaryotic predators or prokaryotic competitors. Killing by the T6SS results from repetitive delivery of toxic effectors. Despite their importance in dictating bacterial fitness, systematic prediction of T6SS effectors remains challenging due to high effector diversity and the absence of a conserved signature sequence. Here, we report a class of T6SS effector chaperone (TEC) proteins that are required for effector delivery through binding to VgrG and effector proteins. The TEC proteins share a highly conserved domain (DUF4123) and are genetically encoded upstream of their cognate effector genes. Using the conserved TEC domain sequence, we identified a large family of TEC genes coupled to putative T6SS effectors in Gram-negative bacteria. We validated this approach by verifying a predicted effector TseC in Aeromonas hydrophila. We show that TseC is a T6SS-secreted antibacterial effector and that the downstream gene tsiC encodes the cognate immunity protein. Further, we demonstrate that TseC secretion requires its cognate TEC protein and an associated VgrG protein.Distinct from previous effector-dependent bioinformatic analyses, our approach using the conserved TEC domain will facilitate the discovery and functional characterization of new T6SS effectors in Gram-negative bacteria.interspecies interaction | colicin | antitoxin | toxin | protein secretion

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“…Moreover, the isolated ADPribosyltransferase domain of this toxin interacts with Hsp90, CypA, Cyp40, and FKBP51 in vitro and coprecipitates with the ADP-ribosyltransferase domain from intoxicated cells [136]. It is worth mentioning that TccC3 is delivered into the cytosol by a novel pore-forming translocation component, completely different from the B components of C2 and iotalike toxins, as recently described [58,137] and previously introduced in this chapter. This indicates that the Hsp90/PPIase-facilitated membrane translocation of ADP-ribosylating toxins is not restricted to a particular type of translocation pore but seems dependent upon an ADP-ribosyltransferase domain.…”

Section: Cellular Uptake Of Binary Actin Adp-ribosylating Toxins Is Fmentioning

confidence: 78%

ADP-ribosylating toxins modifying the actin cytoskeleton

Barth

Stiles

Popoff

2015

The Comprehensive Sourcebook of Bacterial Protein Toxins

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Mechanism of Tc toxin action revealed in molecular detail

Cited by 154 publications

References 65 publications

Lack of Overt Genome Reduction in the Bryostatin-Producing Bryozoan Symbiont “Candidatus Endobugula sertula”

Lack of Overt Genome Reduction in the Bryostatin-Producing Bryozoan Symbiont “Candidatus Endobugula sertula”

Identification of divergent type VI secretion effectors using a conserved chaperone domain

ADP-ribosylating toxins modifying the actin cytoskeleton

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