Bacterial RTX Toxins Allow Acute ATP Release from Human Erythrocytes Directly through the Toxin Pore

Skals, Marianne; Bjaelde, Randi G.; Reinholdt, Jesper; Poulsen, Knud; Vad, Brian S.; Otzen, Daniel E.; Leipziger, Jens; Praetorius, Helle A.

doi:10.1074/jbc.m114.571414

Cited by 49 publications

(54 citation statements)

References 65 publications

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“…The authors show that bacterial pores too narrow to allow passage of ATP do not exhibit P2X receptor-dependent amplification of cell lysis (10). In support for this, we have shown that HlyA-induced ATP release is likely to occur directly through the HlyA-pore itself (11). This is exceedingly interesting because it implies that ATP will be released from any cell attacked by HlyA and thus, P2 receptors will be activated in an auto-and paracrine fashion directly subsequent to membrane insertion of HlyA.…”

supporting

confidence: 60%

[Ca2+] Oscillations and IL-6 Release Induced by α-Hemolysin from Escherichia coli Require P2 Receptor Activation in Renal Epithelia

Christensen

Fagerberg

Bruijn

et al. 2015

Journal of Biological Chemistry

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Background:The virulence factor HlyA elicits [Ca 2ϩ ] i oscillations in renal epithelial cells. Results: These oscillations and following IL-6 release are reduced by inhibition or lack of P2Y 2 receptors. Conclusion: The effects of HlyA in renal epithelial cells are mediated by P2Y 2 receptors. Significance: ATP release and P2Y 2 receptor activation are essential parts of the early interaction between Escherichia coli and the renal epithelium.

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supporting

confidence: 60%

[Ca2+] Oscillations and IL-6 Release Induced by α-Hemolysin from Escherichia coli Require P2 Receptor Activation in Renal Epithelia

Christensen

Fagerberg

Bruijn

et al. 2015

Journal of Biological Chemistry

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“…Recent findings indicated that E. coli HlyA and Aggregatibacter actinomycetemcomitans leukotoxin A induce ATP release from RBCs by forming toxin pores, which then acts on P2X1 and P2X7 to mediate hemolysis [27]. Therefore, we tested the role of ATP in ETX-induced hemolysis.…”

Section: Resultsmentioning

confidence: 99%

Hemolysis in human erythrocytes by Clostridium perfringens epsilon toxin requires activation of P2 receptors

et al. 2018

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Epsilon-toxin (ETX) is produced by types B and D strains of Clostridium perfringens, which cause fatal enterotoxaemia in sheep, goats and cattle. Previous studies showed that only a restricted number of cell lines are sensitive to ETX and ETX-induced hemolysis has not previously been reported. In this study, the hemolytic ability of ETX was examined using erythrocytes from 10 species including murine, rabbit, sheep, monkey and human. We found that ETX caused hemolysis in human erythrocytes (HC50 = 0.2 μM) but not erythrocytes from the other test species. Moreover, the mechanism of ETX-induced hemolysis was further explored. Recent studies showed that some bacterial toxins induce hemolysis through purinergic receptor (P2) activation. Hence, the function of purinergic receptors in ETX-induced hemolysis was tested, and we found that the non-selective P2 receptor antagonists PPADS inhibited ETX-induced lysis of human erythrocytes in a concentration-dependent manner, indicating that ETX-induced hemolysis requires activation of purinergic receptors. P2 receptors comprise seven P2X (P2X1–7) and eight P2Y (P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11–P2Y14) receptor subtypes. The pattern of responsiveness to more selective P2-antagonists implies that both P2Y13 and P2X7 receptors are involved in ETX-induced hemolysis in human species. Furthermore, we demonstrated that extracellular ATP is likely not involved in ETX-induced hemolysis and the activation of P2 receptors. These findings clarified the mechanism of ETX-induced hemolysis and provided new insight into the activities and ETX mode of action.

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“…Burnstock's early hypothesis that ATP, the major intracellular molecule providing the energy required for multiple biochemical and biophysical processes, may actually function as an extracellular non-adrenergic and noncholinergic signaling molecule [12,13] was received with great skepticism [14,15]. After several decades of extensive work, the scientific community came to the realization that ATP is widely employed as a signaling molecule in multiple biological processes in both normal and pathophysiological conditions [9,11,[16][17][18][19][20][21][22][23][24]. The rapid progress in understanding and deciphering multiple molecular mechanisms of signaling revealed that ATP is a potent mediator of multiple signaling cascades, which may act through binding to, and nonhydrolytic activation of, P2X ionotropic receptors or G Electronic supplementary material The online version of this article (doi:10.1007/s11302-016-9520-9) contains supplementary material, which is available to authorized users.…”

Section: Introductionmentioning

confidence: 99%

“…Although multiple past studies focused on understanding the implications of ATP-controlled signaling with respect to endogenous transmembrane transporters such as ion channels [17,19,20,24,[28][29][30][31], there is a recent interest in understanding how ATP controls the lytic action of pore-forming toxins (PFTs) [22,26,27,[32][33][34]. PFTs introduce unregulated conducting pathways into the host cell plasmalemma [35][36][37][38][39], which is expected to yield direct cytolysis.…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies have clearly demonstrated that some PFTs may trigger an early acute release of intracellular ATP through the inserted pores, which further activates the ionotropic P2X receptors and consequently leads to later lysis via the increase of overall membrane permeability to cations such as K + and Ca 2+ [22,26,27,34]. This multistep mechanism is supported by studies in which PFT-mediated ATP transport across artificial vesicle membranes (which are devoid of any other channels or transporters) has been observed, whereas the direct lytic activity presented by the PFTs was minimal [22]. In addition, inhibition of cell lysis in the presence of ATP receptor antagonists demonstrated that a purinergic signaling pathway is responsible for the cell damage [26].…”

Section: Introductionmentioning

confidence: 99%

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Purinergic control of lysenin’s transport and voltage-gating properties

Bryant

Shrestha

Carnig

et al. 2016

Purinergic Signalling

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Lysenin, a pore-forming protein extracted from the coelomic fluid of the earthworm Eisenia foetida, manifests cytolytic activity by inserting large conductance pores in host membranes containing sphingomyelin. In the present study, we found that adenosine phosphates control the biological activity of lysenin channels inserted into planar lipid membranes with respect to their macroscopic conductance and voltage-induced gating. Addition of ATP, ADP, or AMP decreased the macroscopic conductance of lysenin channels in a concentration-dependent manner, with ATP being the most potent inhibitor and AMP the least. ATP removal from the bulk solutions by buffer exchange quickly reinstated the macroscopic conductance and demonstrated reversibility. Singlechannel experiments pointed to an inhibition mechanism that most probably relies on electrostatic binding and partial occlusion of the channel-conducting pathway, rather than ligand gating induced by the highly charged phosphates. The Hill analysis of the changes in macroscopic conduction as a function of the inhibitor concentration suggested cooperative binding as descriptive of the inhibition process. Ionic screening significantly reduced the ATP inhibitory efficacy, in support of the electrostatic binding hypothesis. In addition to conductance modulation, purinergic control over the biological activity of lysenin channels has also been observed to manifest as changes of the voltage-induced gating profile. Our analysis strongly suggests that not only the inhibitor's charge but also its ability to adopt a folded conformation may explain the differences in the observed influence of ATP, ADP, and AMP on lysenin's biological activity.

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Bacterial RTX Toxins Allow Acute ATP Release from Human Erythrocytes Directly through the Toxin Pore

Cited by 49 publications

References 65 publications

[Ca2+] Oscillations and IL-6 Release Induced by α-Hemolysin from Escherichia coli Require P2 Receptor Activation in Renal Epithelia

[Ca2+] Oscillations and IL-6 Release Induced by α-Hemolysin from Escherichia coli Require P2 Receptor Activation in Renal Epithelia

Hemolysis in human erythrocytes by Clostridium perfringens epsilon toxin requires activation of P2 receptors

Purinergic control of lysenin’s transport and voltage-gating properties

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