Differences in Cytotoxicity of Native and Engineered RIPs Can Be Used to Assess Their Ability to Reach the Cytoplasm

Svinth, M.; Steighardt, Jörg; Hernandez, Raquel; Suh, Jung Keun; Kelly, C. E.; Day, Philip J.; Lord, Michael J.; Girbés, Tomás; Robertus, Jon D.

doi:10.1006/bbrc.1998.9207

Cited by 28 publications

(20 citation statements)

References 35 publications

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“…Both the native [92,93] and the recombinant [94] A chains of the agglutinin are 15-and 11-fold, respectively, less active in inhibiting cell-free protein synthesis than the A chains of native and recombinant ricin. The reduced toxicity of RCA may be due to its reduced capacity to translocate [95], and that of ebulin, another nontoxic type 2 RIP, from S. ebulus, to its reduced affinity for galactose [96]. These differences, however, are of one order of magnitude, approximately, thus not accounting for the much higher toxicity of ricin compared with the agglutinin.…”

Section: Toxic and Non-toxic Type 2 Ripsmentioning

confidence: 99%

“…These differences, however, are of one order of magnitude, approximately, thus not accounting for the much higher toxicity of ricin compared with the agglutinin. Furthermore, ricin is some 68-fold more toxic to cells than RCA [95], but some 2000-fold more toxic to mice [97]. The hypothesis was formulated [98] that, although both lectins can bind to serum glycoproteins and red blood cells, only the agglutinin, being divalent, can form precipitates or agglutinate red cells, thus being prevented from reaching cells in vital organs.…”

Section: Toxic and Non-toxic Type 2 Ripsmentioning

confidence: 99%

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Ribosome-inactivating proteins: progress and problems

Stirpe

Battelli

2006

Cell. Mol. Life Sci.

318

225

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Ribosome-inactivating proteins (RIPs), mostly from plants, are enzymes which depurinate rRNA, thus inhibiting protein synthesis. They also depurinate other polynucleotide substrates. The biological activity of RIPs is not completely clarified, and sometimes independent of the inhibition of protein synthesis. There are differences in the cytotoxicity of RIPs and, consequently, in their toxicity to animals. Some RIPs are potent toxins, the best known being ricin, a potential biological weapon. New toxins have recently been identified. RIPs cause apoptotic and necrotic lesions, and induce production of cytokines causing inflammation. RIPs are potentially useful in agriculture and medicine because (i) they have antiviral activity and (ii) they are used for the preparation of conjugates with antibodies ('immunotoxins') or other carriers, rendering them specifically toxic to the cell target of the carrier, which may be helpful in therapy. The distribution, mechanism of action and role in nature of RIPs are not completely understood, and we can expect several future developments in their practical application.

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Section: Toxic and Non-toxic Type 2 Ripsmentioning

confidence: 99%

Section: Toxic and Non-toxic Type 2 Ripsmentioning

confidence: 99%

Ribosome-inactivating proteins: progress and problems

Stirpe

Battelli

2006

Cell. Mol. Life Sci.

318

225

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“…These differences cannot be explained by diversity in the catalytic activity of the A chains, which all efficiently inhibit cell-free protein synthesis. They could, rather, be due to differences between their B chains [19], which mediate the interaction with cells, in particular (i) binding to the cell membrane, (ii) the uptake by cells, (iii) the intracellular routeing, (iv) the degree of degradation and (v) the exocytosis of the toxin by cells. The mechanism of entry and intracellular routeing of ricin has been extensively studied.…”

mentioning

confidence: 99%

Interaction of volkensin with HeLa cells: binding, uptake, intracellular localization, degradation and exocytosis

Battelli

Musiani

Buonamici

et al. 2004

Cell. Mol. Life Sci.

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Among two-chain ribosome-inactivating proteins (RIPs), volkensin is the most toxic to cells and animals, and is retrogradely axonally transported in the rat central nervous system, being an effective suicide transport agent. Here we studied the binding, endocytosis, intracellular routeing, degradation and exocytosis of this RIP. The interaction of volkensin with HeLa cells was compared to that of nigrin b, as an example of a type 2 RIP with low toxicity, and of ricin, as a reference toxin. Nigrin b and volkensin bound to cells with comparable affinity (approx. 10(-10) M) and had a similar number of binding sites (2 x 10(5)/cell), two-log lower than that reported for ricin. The cellular uptake of volkensin was lower than that reported for nigrin b and ricin. Confocal microscopy showed the rapid localization of volkensin in the Golgi stacks with a perinuclear localization similar to that of ricin, while nigrin b was distributed between cytoplasmic dots and the Golgi compartment. Consistently, brefeldin A, which disrupts the Golgi apparatus, protected cells from the inhibition of protein synthesis by volkensin or ricin, whereas it was ineffective in the case of nigrin b. Of the cell-released RIPs, 57% of volkensin and only 5% of ricin were active, whilst exocytosed nigrin b was totally inactive. Despite the low binding to, and uptake by, cells, the high cytotoxicity of volkensin may depend on (i) routeing to the Golgi apparatus, (ii) the low level of degradation, (iii) rapid recycling and (iv) the high percentage of active toxin remaining after exocytosis.

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“…This seems an essential difference between the Sambucus proteins and the ricin which could be related to the low cell toxicity of ebulin l as compared with ricin. The pathway followed by both ricin and ebulin l is determined by the features of the corresponding B chain (Svinth et al, 1998). The temperature-dependent differences may reflect a differential interaction of the two RIPs with glycosylated receptors of the plasma membrane as has been hypothesized for the closely related RIP nigrin b Battelli et al, 2004).…”

Section: Resultsmentioning

confidence: 96%