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Current Opinion in Cell Biology Aug 2016Bacterial toxins often translocate across a cellular membrane to gain access into the host cytosol, modifying cellular components in order to exert their toxic effects.... (Review)
Review
Bacterial toxins often translocate across a cellular membrane to gain access into the host cytosol, modifying cellular components in order to exert their toxic effects. To accomplish this feat, these toxins traffic to a membrane penetration site where they undergo conformational changes essential to eject the toxin's catalytic subunit into the cytosol. In this brief review, we highlight recent findings that elucidate both the trafficking pathways and membrane translocation mechanisms of toxins that cross the plasma, endosomal, or endoplasmic reticulum (ER) membrane. These findings not only illuminate the specific nature of the host-toxin interactions during entry, but should also provide additional therapeutic strategies to prevent or alleviate the bacterial toxin-induced diseases.
Topics: Animals; Bacterial Toxins; Cell Membrane; Endoplasmic Reticulum; Endosomes; Humans; Intracellular Membranes; Intracellular Space; Protein Transport
PubMed: 27084982
DOI: 10.1016/j.ceb.2016.03.019 -
FEMS Microbiology Reviews Sep 2023Toxin-antitoxin (TA) systems are entities found in the prokaryotic genomes, with eight reported types. Type II, the best characterized, is comprised of two genes...
Toxin-antitoxin (TA) systems are entities found in the prokaryotic genomes, with eight reported types. Type II, the best characterized, is comprised of two genes organized as an operon. Whereas toxins impair growth, the cognate antitoxin neutralizes its activity. TAs appeared to be involved in plasmid maintenance, persistence, virulence, and defence against bacteriophages. Most Type II toxins target the bacterial translational machinery. They seem to be antecessors of Higher Eukaryotes and Prokaryotes Nucleotide-binding (HEPN) RNases, minimal nucleotidyltransferase domains, or CRISPR-Cas systems. A total of four TAs encoded by Streptococcus pneumoniae, RelBE, YefMYoeB, Phd-Doc, and HicAB, belong to HEPN-RNases. The fifth is represented by PezAT/Epsilon-Zeta. PezT/Zeta toxins phosphorylate the peptidoglycan precursors, thereby blocking cell wall synthesis. We explore the body of knowledge (facts) and hypotheses procured for Type II TAs and analyse the data accumulated on the PezAT family. Bioinformatics analyses showed that homologues of PezT/Zeta toxin are abundantly distributed among 14 bacterial phyla mostly in Proteobacteria (48%), Firmicutes (27%), and Actinobacteria (18%), showing the widespread distribution of this TA. The pezAT locus was found to be mainly chromosomally encoded whereas its homologue, the tripartite omega-epsilon-zeta locus, was found mostly on plasmids. We found several orphan pezT/zeta toxins, unaccompanied by a cognate antitoxin.
Topics: Antitoxins; Bacterial Toxins; Bacteria; Operon; Prokaryotic Cells; Bacterial Proteins
PubMed: 37715317
DOI: 10.1093/femsre/fuad052 -
Current Topics in Microbiology and... 2017Rational design of multivalent molecules represents a remarkable modern tool to transform weak non-covalent interactions into strong binding by creating multiple... (Review)
Review
Rational design of multivalent molecules represents a remarkable modern tool to transform weak non-covalent interactions into strong binding by creating multiple finely-tuned points of contact between multivalent ligands and their supposed multivalent targets. Here, we describe several prominent examples where the multivalent blockers were investigated for their ability to directly obstruct oligomeric channel-forming bacterial exotoxins, such as the pore-forming bacterial toxins and B component of the binary bacterial toxins. We address problems related to the blocker/target symmetry match and nature of the functional groups, as well as chemistry and length of the linkers connecting the functional groups to their multivalent scaffolds. Using the anthrax toxin and AB5 toxin case studies, we briefly review how the oligomeric toxin components can be successfully disabled by the multivalent non-channel-blocking inhibitors, which are based on a variety of multivalent scaffolds.
Topics: Antigens, Bacterial; Bacterial Toxins; Ligands
PubMed: 27469304
DOI: 10.1007/82_2016_20 -
Toxins Apr 2018Cyclomodulins are bacterial toxins that interfere with the eukaryotic cell cycle. A new cyclomodulin called colibactin, which is synthetized by the genomic island, was... (Review)
Review
Cyclomodulins are bacterial toxins that interfere with the eukaryotic cell cycle. A new cyclomodulin called colibactin, which is synthetized by the genomic island, was discovered in 2006. Despite many efforts, colibactin has not yet been purified, and its structure remains elusive. Interestingly, the island is found in members of the family (mainly and ) isolated from different origins, including from intestinal microbiota, septicaemia, newborn meningitis, and urinary tract infections. Colibactin-producing bacteria induce chromosomal instability and DNA damage in eukaryotic cells, which leads to senescence of epithelial cells and apoptosis of immune cells. The island is mainly observed in B2 phylogroup strains, which include extra-intestinal pathogenic strains, and are over-represented in biopsies isolated from colorectal cancer. In addition, bacteria increase the number of tumours in diverse colorectal cancer mouse models. Thus, colibactin could have a major impact on human health. In the present review, we will focus on the biological effects of colibactin, the distribution of the island, and summarize what is currently known about its synthesis and its structure.
Topics: Animals; Bacterial Toxins; Genomic Islands; Humans; Mutagens; Peptides; Polyketides
PubMed: 29642622
DOI: 10.3390/toxins10040151 -
Molecular Cell Jun 2018Bacterial toxin-antitoxin (TA) modules are abundant genetic elements that encode a toxin protein capable of inhibiting cell growth and an antitoxin that counteracts the... (Review)
Review
Bacterial toxin-antitoxin (TA) modules are abundant genetic elements that encode a toxin protein capable of inhibiting cell growth and an antitoxin that counteracts the toxin. The majority of toxins are enzymes that interfere with translation or DNA replication, but a wide variety of molecular activities and cellular targets have been described. Antitoxins are proteins or RNAs that often control their cognate toxins through direct interactions and, in conjunction with other signaling elements, through transcriptional and translational regulation of TA module expression. Three major biological functions of TA modules have been discovered, post-segregational killing ("plasmid addiction"), abortive infection (bacteriophage immunity through altruistic suicide), and persister formation (antibiotic tolerance through dormancy). In this review, we summarize the current state of the field and highlight how multiple levels of regulation shape the conditions of toxin activation to achieve the different biological functions of TA modules.
Topics: Antitoxins; Bacteria; Bacterial Proteins; Bacterial Toxins; Drug Resistance, Bacterial; Evolution, Molecular; Gene Expression Regulation, Bacterial; Immunity, Innate; Microbial Viability; Models, Molecular; Nucleic Acid Conformation; Protein Conformation; RNA Processing, Post-Transcriptional; RNA, Bacterial; Structure-Activity Relationship; Transcription, Genetic
PubMed: 29398446
DOI: 10.1016/j.molcel.2018.01.003 -
Toxins Jan 2019Toxins can function both as a harmful and therapeutic molecule, depending on their concentrations. The diversity in their function allows us to ask some very pertinent... (Review)
Review
Toxins can function both as a harmful and therapeutic molecule, depending on their concentrations. The diversity in their function allows us to ask some very pertinent questions related to their origin and roles: (a) What makes them such effective molecules? (b) Are there evolutionary features encoded within the structures of the toxins for their function? (c) Is structural hierarchy in the toxins important for maintaining their structure and function? (d) Do protein dynamics play a role in the function of toxins? and (e) Do the evolutionary connections to these unique features and functions provide the fundamental points in driving evolution? In light of the growing evidence in structural biology, it would be appropriate to suggest that protein dynamics and flexibility play a much bigger role in the function of the toxin than the structure itself. Discovery of IDPs (intrinsically disorder proteins), multifunctionality, and the concept of native aggregation are shaking the paradigm of the requirement of a fixed three-dimensional structure for the protein's function. Growing evidence supporting the above concepts allow us to redesign the structure-function aspects of the protein molecules. An evolutionary model is necessary and needs to be developed to study these important aspects. The criteria for a well-defined model would be: (a) diversity in structure and function, (b) unique functionality, and (c) must belong to a family to define the evolutionary relationships. All these characteristics are largely fulfilled by bacterial toxins. Bacterial toxins are diverse and widely distributed in all three forms of life (Bacteria, Archaea and Eukaryotes). Some of the unique characteristics include structural folding, sequence and functional combination of domains, targeting a cellular process to execute their function, and most importantly their flexibility and dynamics. In this work, we summarize certain unique aspects of bacterial toxins, including role of structure in defining toxin function, uniqueness in their enzymatic function, and interaction with their substrates and other proteins. Finally, we have discussed the evolutionary aspects of toxins in detail, which will help us rethink the current evolutionary theories. A careful study, and appropriate interpretations, will provide answers to several questions related to the structure-function relationship of proteins, in general. Additionally, this will also allow us to refine the current evolution theories.
Topics: Bacterial Toxins; Evolution, Molecular; Humans; Proteins
PubMed: 30609803
DOI: 10.3390/toxins11010015 -
Pathogens and Disease Dec 2015Bacteria frequently manipulate their host environment via delivery of microbial 'effector' proteins to the cytosol of eukaryotic cells. In the case of the... (Review)
Review
Bacteria frequently manipulate their host environment via delivery of microbial 'effector' proteins to the cytosol of eukaryotic cells. In the case of the multifunctional autoprocessing repeats-in-toxins (MARTX) toxin, this phenomenon is accomplished by a single, >3500 amino acid polypeptide that carries information for secretion, translocation, autoprocessing and effector activity. MARTX toxins are secreted from bacteria by dedicated Type I secretion systems. The released MARTX toxins form pores in target eukaryotic cell membranes for the delivery of up to five cytopathic effectors, each of which disrupts a key cellular process. Targeted cellular processes include modulation or modification of small GTPases, manipulation of host cell signaling and disruption of cytoskeletal integrity. More recently, MARTX toxins have been shown to be capable of heterologous protein translocation. Found across multiple bacterial species and genera--frequently in pathogens lacking Type 3 or Type 4 secretion systems--MARTX toxins in multiple cases function as virulence factors. Innovative research at the intersection of toxin biology and bacterial genetics continues to elucidate the intricacies of the toxin as well as the cytotoxic mechanisms of its diverse effector collection.
Topics: Animals; Bacterial Toxins; Humans; Models, Biological; Models, Molecular; Protein Transport; Virulence Factors
PubMed: 26472741
DOI: 10.1093/femspd/ftv092 -
Molecular Microbiology Jan 2018Bacteria often coordinate virulence factors to fine-tune the host response during infection. These coordinated events can include toxins counteracting or amplifying... (Review)
Review
Bacteria often coordinate virulence factors to fine-tune the host response during infection. These coordinated events can include toxins counteracting or amplifying effects of another toxin or though regulating the stability of virulence factors to remove their function once it is no longer needed. Multifunctional autoprocessing repeats-in toxin (MARTX) toxins are effector delivery toxins that form a pore into the plasma membrane of a eukaryotic cell to deliver multiple effector proteins into the cytosol of the target cell. The function of these proteins includes manipulating actin cytoskeletal dynamics, regulating signal transduction pathways and inhibiting host secretory pathways. Investigations into the molecular mechanisms of these effector domains are providing insight into how the function of some effectors overlap and regulate one another during infection. Coordinated crosstalk of effector function suggests that MARTX toxins are not simply a sum of all their parts. Instead, modulation of cell function by effector domains may depend on which other effector domain are co-delivered. Future studies will elucidate how these effectors interact with each other to modulate the bacterial host interaction.
Topics: Actin Cytoskeleton; Autophagy; Bacteria; Bacterial Toxins; Cell Membrane; Eukaryotic Cells; Host Microbial Interactions; Humans; Secretory Pathway; Type III Secretion Systems; Virulence
PubMed: 29114985
DOI: 10.1111/mmi.13875 -
Wiley Interdisciplinary Reviews. RNA Jan 2019Prokaryotic toxin-antitoxin (TA) systems are composed of a protein toxin and its cognate antitoxin. These systems are abundant in bacteria and archaea and play an... (Review)
Review
Prokaryotic toxin-antitoxin (TA) systems are composed of a protein toxin and its cognate antitoxin. These systems are abundant in bacteria and archaea and play an important role in growth regulation. During favorable growth conditions, the antitoxin neutralizes the toxin's activity. However, during conditions of stress or starvation, the antitoxin is inactivated, freeing the toxin to inhibit growth and resulting in dormancy. One mechanism of growth inhibition used by several TA systems results from targeting transfer RNAs (tRNAs), either through preventing aminoacylation, acetylating the primary amino group, or endonucleolytic cleavage. All of these mechanisms inhibit translation and result in growth arrest. Many of these toxins only act on a specific tRNA or a specific subset of tRNAs; however, more work is necessary to understand the specificity determinants of these toxins. For the toxins whose specificity has been characterized, both sequence and structural components of the tRNA appear important for recognition by the toxin. Questions also remain regarding the mechanisms used by dormant bacteria to resume growth after toxin induction. Rescue of stalled ribosomes by transfer-messenger RNAs, removal of acetylated amino groups from tRNAs, or ligation of cleaved RNA fragments have all been implicated as mechanisms for reversing toxin-induced dormancy. However, the mechanisms of resuming growth after induction of the majority of tRNA targeting toxins are not yet understood. This article is categorized under: Translation > Translation Regulation RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition.
Topics: Bacterial Toxins; Protein Biosynthesis; RNA, Transfer; Toxin-Antitoxin Systems
PubMed: 30296016
DOI: 10.1002/wrna.1506 -
Experimental Biology and Medicine... Jun 2016Toxin-antitoxin systems are encoded by bacteria and archaea to enable an immediate response to environmental stresses, including antibiotics and the host immune... (Review)
Review
Toxin-antitoxin systems are encoded by bacteria and archaea to enable an immediate response to environmental stresses, including antibiotics and the host immune response. During normal conditions, the antitoxin components prevent toxins from interfering with metabolism and arresting growth; however, toxin activation enables microbes to remain dormant through unfavorable conditions that might continue over millions of years. Intense investigations have revealed a multitude of mechanisms for both regulation and activation of toxin-antitoxin systems, which are abundant in pathogenic microorganisms. This minireview provides an overview of the current knowledge regarding type II toxin-antitoxin systems along with their clinical and environmental implications.
Topics: Archaea; Bacteria; Bacterial Proteins; Bacterial Toxins
PubMed: 27216598
DOI: 10.1177/1535370216651938