Ricin and Shiga Toxins: Effects on Host Cell Signal Transduction

Jandhyala, Dakshina M.; Thorpe, Cheleste M.; Magun, Bruce E.

doi:10.1007/82_2011_181

Cited by 30 publications

(40 citation statements)

References 128 publications

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“…Once in the endoplasmic reticulum, the ricin A subunit (RTA) is liberated from RTB and is dislocated across the endoplasmic reticulum membrane into the cytoplasm, where it functions as an RNA N-glycosidase whose sole substrate is a universally conserved adenosine residue within the so-called sarcin/ricin loop of mammalian rRNA (5). Hydrolysis of the sarcin/ricin loop by RTA results in the cessation of cellular protein synthesis, activation of the ribotoxic stress response, and cell death via apoptosis (6).…”

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confidence: 99%

Stepwise Engineering of Heterodimeric Single Domain Camelid VHH Antibodies That Passively Protect Mice from Ricin Toxin

Vance

Tremblay

Mantis

et al. 2013

Journal of Biological Chemistry

130

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Background:We sought to engineer highly efficacious agents that neutralize ricin toxin. Results: We identified monomeric single-chain camelid V H domains (V H Hs) capable of neutralizing ricin in vitro and engineered heterodimeric V H Hs that neutralized ricin in vivo. Conclusion: Stepwise engineering of V H Hs resulted in highly potent ricin toxin-neutralizing antibodies. Significance: This study highlights the potential use of a V H H platform as a strategy for therapeutics against diverse biological toxins.

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confidence: 99%

Stepwise Engineering of Heterodimeric Single Domain Camelid VHH Antibodies That Passively Protect Mice from Ricin Toxin

Vance

Tremblay

Mantis

et al. 2013

Journal of Biological Chemistry

130

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“…For example, several studies have demonstrated that intoxication with Stx activates proinflammatory and proapoptotic signaling pathways (60,61), in part through the activation of the MAPK pathway (62)(63)(64). This activation of the RSR contributes to both proinflammatory and proapoptotic signaling in cultured cells (62,63,65,66).…”

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confidence: 99%

Effects of Shiga Toxin Type 2 on a Bioengineered Three-Dimensional Model of Human Renal Tissue

et al. 2015

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dShiga toxins (Stx) are a family of cytotoxic proteins that can cause hemolytic-uremic syndrome (HUS), a thrombotic microangiopathy, following infections by Shiga toxin-producing Escherichia coli (STEC). Renal failure is a key feature of HUS and a major cause of childhood renal failure worldwide. There are currently no specific therapies for STEC-associated HUS, and the mechanism of Stx-induced renal injury is not well understood primarily due to a lack of fully representative animal models and an inability to monitor disease progression on a molecular or cellular level in humans at early stages. Three-dimensional (3D) tissue models have been shown to be more in vivo-like in their phenotype and physiology than 2D cultures for numerous disease models, including cancer and polycystic kidney disease. It is unknown whether exposure of a 3D renal tissue model to Stx will yield a more in vivo-like response than 2D cell culture. In this study, we characterized Stx2-mediated cytotoxicity in a bioengineered 3D human renal tissue model previously shown to be a predictor of drug-induced nephrotoxicity and compared its response to Stx2 exposure in 2D cell culture. Our results demonstrate that although many mechanistic aspects of cytotoxicity were similar between 3D and 2D, treatment of the 3D tissues with Stx resulted in an elevated secretion of the kidney injury marker 1 (Kim-1) and the cytokine interleukin-8 compared to the 2D cell cultures. This study represents the first application of 3D tissues for the study of Stx-mediated kidney injury.

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“…RTA is then dislocated (retro-translocated) across the ER membrane with the assistance of the ER-associated protein degradation system. Once in the cytoplasm, RTA triggers ribosome inactivation and programmed cell death (5). Structurally, RTA is a globular protein that can be divided into three distinct folding domains (6).…”

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confidence: 99%

“…5 Another group has reported the X-ray crystal structure of a Fab fragment in complex with cluster I (19). At the structural level, cluster I epitopes encompass ␣-helix B (residues 98 -106), ␤-strand h (residues 113-117), and the C terminus of ␣-helix D (residues 154 -156).…”

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confidence: 99%

“…We subsequently identified three additional toxin-neutralizing mAbs, TB12, PA1, and PH12, that recognize discontinuous epitopes within cluster II (14). The epitopes recognized by SyH7, TB12, PA1, and PH12 are distinct from each other, as determined by HX-MS. 5 Because all four cluster II mAbs neutralize ricin in vitro and in vivo, we have proposed that their epitopes represent a particular site of vulnerability on the toxin. We report here the X-ray crystal structures of three different cluster II V H Hs in complex with RTA, including one V H H whose epitope possibly spans the interface between RTA and RTB.…”

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confidence: 99%

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Structural Analysis of Single Domain Antibodies Bound to a Second Neutralizing Hot Spot on Ricin Toxin's Enzymatic Subunit

Rudolph

Vance

Cassidy

et al. 2017

Journal of Biological Chemistry

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Edited by Peter CresswellRicin toxin is a heterodimer consisting of RTA, a ribosomeinactivating protein, and RTB, a lectin that facilitates receptormediated uptake into mammalian cells. In previous studies, we demonstrated that toxin-neutralizing antibodies target four spatially distinct hot spots on RTA, which we refer to as epitope clusters I-IV. In this report, we identified and characterized three single domain camelid antibodies (V H H) against cluster II. One of these V H Hs, V5E1, ranks as one of the most potent ricinneutralizing antibodies described to date. We solved the X-ray crystal structures of each of the three V H Hs (E1, V1C7, and V5E1) in complex with RTA. V5E1 buries a total of 1,133 Å 2 of surface area on RTA and makes primary contacts with ␣-helix A (residues 18 -32), ␣-helix F (182-194), as well as the F-G loop. V5E1, by virtue of complementarity determining region 3 (CDR3), may also engage with RTB and potentially interfere with the high affinity galactose-recognition element that plays a critical role in toxin attachment to cell surfaces and intracellular trafficking. The two other V H Hs, E1 and V1C7, bind epitopes adjacent to V5E1 but display only weak toxin neutralizing activity, thereby providing structural insights into specific residues within cluster II that may be critical contact points for toxin inactivation.

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Ricin and Shiga Toxins: Effects on Host Cell Signal Transduction

Cited by 30 publications

References 128 publications

Stepwise Engineering of Heterodimeric Single Domain Camelid VHH Antibodies That Passively Protect Mice from Ricin Toxin

Stepwise Engineering of Heterodimeric Single Domain Camelid VHH Antibodies That Passively Protect Mice from Ricin Toxin

Effects of Shiga Toxin Type 2 on a Bioengineered Three-Dimensional Model of Human Renal Tissue

Structural Analysis of Single Domain Antibodies Bound to a Second Neutralizing Hot Spot on Ricin Toxin's Enzymatic Subunit

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