Post‐translational acylation controls the folding and functions of the CyaA RTX toxin

O’Brien, Darragh P.; Cannella, Sara; Voegele, Alexis; Raoux-Barbot, Dorothée; Davi, Marilyne; Douché, Thibaut; Matondo, Mariette; Brier, Sébastien; Ladant, Daniel; Chenal, Alexandre

doi:10.1096/fj.201802442rr

Cited by 24 publications

(26 citation statements)

References 59 publications

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“…Importantly, a significant amount of heterogeneity was observed in the acylation patterns of LtxA (Fong et al, 2011), but the process of acylation of internal lysine residues by 14–18 carbon fatty acids is conserved among several RTX toxins, including E. coli HlyA (Lim et al, 2000; Ludwig et al, 1996) and Bordetella pertussis adenylate cyclase toxin (CyaA; Hackett, Guo, Shabanowitz, Hunt, & Hewlett, 1994; Masin et al, 2005). Acylation of the RTX toxins has been demonstrated to be required for host cell toxicity (Basar, Havlicek, Bezouskova, Hackett, & Sebo, 2001; Fong et al, 2011; Masin et al, 2005; Stanley, Packman, Koronakis, & Hughes, 1994), but the exact role of these hydrocarbon chains in host cell toxicity have not been rigorously tested, until recently when O’Brien et al demonstrated, using a comprehensive mass spectrometry‐based approach, that the acyl chains of CyaA affect toxin folding and stability (O’Brien et al, 2019). Future work may demonstrate a similar role in other RTX toxins, including LtxA.…”

Section: Ltxa Expression/secretionmentioning

confidence: 99%

Aggregatibacter actinomycetemcomitans leukotoxin: From mechanism to targeted anti‐toxin therapeutics

Krueger

Brown

2020

Molecular Oral Microbiology

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Aggregatibacter actinomycetemcomitans is a Gram-negative bacterium associated with localized aggressive periodontitis, as well as other systemic diseases. This organism produces a number of virulence factors, all of which provide some advantage to the bacterium. Several studies have demonstrated that clinical isolates from diseased patients, particularly those of African descent, frequently belong to specific clones of A. actinomycetemcomitans that produce significantly higher amounts of a protein exotoxin belonging to the repeats-in-toxin (RTX) family, leukotoxin (LtxA), whereas isolates from healthy patients harbor minimally leukotoxic strains. This finding suggests that LtxA might play a key role in A. actinomycetemcomitans pathogenicity. Because of this correlation, much work over the past 30 years has been focused on understanding the mechanisms by which LtxA interacts with and kills host cells.In this article, we review those findings, highlight the remaining open questions, and demonstrate how knowledge of these mechanisms, particularly the toxin's interactions with lymphocyte function-associated antigen-1 (LFA-1) and cholesterol, enables the design of targeted anti-LtxA strategies to prevent/treat disease. K E Y W O R D SAggregatibacter actinomycetemcomitans, leukotoxin, LFA-1, repeats-in-toxin

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Section: Ltxa Expression/secretionmentioning

confidence: 99%

Aggregatibacter actinomycetemcomitans leukotoxin: From mechanism to targeted anti‐toxin therapeutics

Krueger

Brown

2020

Molecular Oral Microbiology

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“…At sublytic concentrations, RTX toxins bind to β 2 -integrins and induce signaling cascades leading to apoptosis that results in inflammation, tissue lesions, and, finally, to disease [22][23][24][25][26][27]. Initial contact and binding of RTX proteins with their targets were shown to require acylation of two specific lysine sites that leads to a conformational stabilization of the protein and Ca 2+ binding at the glycine-rich nonapeptide repeats [28][29][30][31].…”

Section: Avxmentioning

confidence: 99%

RTX Toxins of Animal Pathogens and Their Role as Antigens in Vaccines and Diagnostics

Frey

2019

Toxins

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Exotoxins play a central role in the pathologies caused by most major bacterial animal pathogens. The large variety of vertebrate and invertebrate hosts in the animal kingdom is reflected by a large variety of bacterial pathogens and toxins. The group of repeats in the structural toxin (RTX) toxins is particularly abundant among bacterial pathogens of animals. Many of these toxins are described as hemolysins due to their capacity to lyse erythrocytes in vitro. Hemolysis by RTX toxins is due to the formation of cation-selective pores in the cell membrane and serves as an important marker for virulence in bacterial diagnostics. However, their physiologic relevant targets are leukocytes expressing β2 integrins, which act as specific receptors for RTX toxins. For various RTX toxins, the binding to the CD18 moiety of β2 integrins has been shown to be host specific, reflecting the molecular basis of the host range of RTX toxins expressed by bacterial pathogens. Due to the key role of RTX toxins in the pathogenesis of many bacteria, antibodies directed against specific RTX toxins protect against disease, hence, making RTX toxins valuable targets in vaccine research and development. Due to their specificity, several structural genes encoding for RTX toxins have proven to be essential in modern diagnostic applications in veterinary medicine.

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“…The purity of CyaA batches is higher than 90% as judged by SDS PAGE analysis and contained less than 1 EU of LPS/μg of protein as determined by a standard LAL assay (Lonza). Finally, CyaA is refolded into a urea-free, monomeric and functional holo-state [31,32]. The refolding efficiency is around 40±5% (population monomer / total population of proteins).…”

Section: Introductionmentioning

confidence: 99%

Functional and structural consequences of epithelial cell invasion by Bordetella pertussis adenylate cyclase toxin

et al. 2020

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Bordetella pertussis, the causative agent of whopping cough, produces an adenylate cyclase toxin (CyaA) that plays a key role in the host colonization by targeting innate immune cells which express CD11b/CD18, the cellular receptor of CyaA. CyaA is also able to invade non-phagocytic cells, via a unique entry pathway consisting in a direct translocation of its catalytic domain across the cytoplasmic membrane of the cells. Within the cells, CyaA is activated by calmodulin to produce high levels of cyclic adenosine monophosphate (cAMP) and alter cellular physiology. In this study, we explored the effects of CyaA toxin on the cellular and molecular structure remodeling of A549 alveolar epithelial cells. Using classical imaging techniques, biochemical and functional tests, as well as advanced cell mechanics method, we quantify the structural and functional consequences of the massive increase of intracellular cyclic AMP induced by the toxin: cell shape rounding associated to adhesion weakening process, actin structure remodeling for the cortical and dense components, increase in cytoskeleton stiffness, and inhibition of migration and repair. We also show that, at low concentrations (0.5 nM), CyaA could significantly impair the migration and wound healing capacities of the intoxicated alveolar epithelial cells. As such concentrations might be reached locally during B. pertussis infection, our results suggest that the CyaA, beyond its major role in disabling innate immune cells, might also contribute to the local alteration of the epithelial barrier of the respiratory tract, a hallmark of pertussis.

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Post‐translational acylation controls the folding and functions of the CyaA RTX toxin

Cited by 24 publications

References 59 publications

Aggregatibacter actinomycetemcomitans leukotoxin: From mechanism to targeted anti‐toxin therapeutics

Aggregatibacter actinomycetemcomitans leukotoxin: From mechanism to targeted anti‐toxin therapeutics

RTX Toxins of Animal Pathogens and Their Role as Antigens in Vaccines and Diagnostics

Functional and structural consequences of epithelial cell invasion by Bordetella pertussis adenylate cyclase toxin

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