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PMID:22228764

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Citation

Pasetto, M, Barison, E, Castagna, M, Della Cristina, P, Anselmi, C and Colombatti, M (2012) Reductive activation of type 2 ribosome-inactivating proteins is promoted by transmembrane thioredoxin-related protein. J. Biol. Chem. 287:7367-73

Abstract

Members of the type 2 ribosome-inactivating proteins (RIPs) family (e.g. ricin, abrin) are potent cytotoxins showing a strong lethal activity toward eukaryotic cells. Type 2 RIPs contain two polypeptide chains (usually named A, for "activity", and B, for "binding") linked by a disulfide bond. The intoxication of the cell is a consequence of a reductive process in which the toxic domain is cleaved from the binding domain by oxidoreductases located in the lumen of the endoplasmic reticulum (ER). The best known example of type 2 RIPs is ricin. Protein disulfide isomerase (PDI) was demonstrated to be involved in the process of ricin reduction; however, when PDI is depleted from cell fraction preparations ricin reduction can still take place, indicating that also other oxidoreductases might be implicated in this process. We have investigated the role of TMX, a transmembrane thioredoxin-related protein member of the PDI family, in the cell intoxication operated by type 2 RIPs ricin and abrin. Overexpressing TMX in A549 cells resulted in a dramatic increase of ricin or abrin cytotoxicity compared with control mock-treated cells. Conversely, no difference in cytotoxicity was observed after treatment of A549 cells or control cells with saporin or Pseudomonas exotoxin A whose intracellular mechanism of activation is not dependent upon reduction (saporin) or only partially dependent upon it (Pseudomonas exotoxin A). Moreover, the silencing of TMX in the prostatic cell line DU145 reduced the sensitivity of the cells to ricin intoxication further confirming a role for this enzyme in intracellular ricin activation.

Links

PubMed PMC3293526 Online version:10.1074/jbc.M111.316828

Keywords

ADP Ribose Transferases/pharmacokinetics; ADP Ribose Transferases/pharmacology; Abrin/pharmacokinetics; Abrin/pharmacology; Bacterial Toxins/pharmacokinetics; Bacterial Toxins/pharmacology; Chemical Warfare Agents/pharmacokinetics; Chemical Warfare Agents/pharmacology; Endoplasmic Reticulum/genetics; Endoplasmic Reticulum/metabolism; Exotoxins/pharmacokinetics; Exotoxins/pharmacology; Humans; Jurkat Cells; Membrane Proteins/genetics; Membrane Proteins/metabolism; Oxidation-Reduction/drug effects; Protein Disulfide-Isomerases/genetics; Protein Disulfide-Isomerases/metabolism; Protein Synthesis Inhibitors/pharmacokinetics; Protein Synthesis Inhibitors/pharmacology; Ribosome Inactivating Proteins, Type 1/pharmacokinetics; Ribosome Inactivating Proteins, Type 1/pharmacology; Ricin/pharmacokinetics; Ricin/pharmacology; Thioredoxins/genetics; Thioredoxins/metabolism; Virulence Factors/pharmacokinetics; Virulence Factors/pharmacology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TMX1

GO:0015036: disulfide oxidoreductase activity

ECO:0000314:

F

In order for Ricin to intoxicate the host cell, its disulfide bridge has to be reduced. It has been shown that protein disulfide isomerase (PDI) has the ability to reduce the disulfide bond. However, reduction can still occur even when PDI is depleted, suggesting that other proteins are also responsible to reduce Ricin. Transmenbrane Thioredoxin related protein (TMX) has been found to reduce Ricin. Figure 2 shows that TMX is needed to reduce Ricin. In Lane 1 when TMX is added, Ricin is reduced (the RTA band), whereas in lane 3 with no TMX, Ricin is not reduced.

complete
CACAO 3765

HUMAN:TMX1

enables

GO:0015036: disulfide oxidoreductase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

ABRPR:ABRA

GO:0031640 : killing of cells of other organism

ECO:0000314:

P

Figure 1B and Table 1.

complete
CACAO 4121

PSEAI:A4K447

GO:0006915: apoptotic process

ECO:0000314:

P

Figure 1C and table 1.

complete
CACAO 4604

SAPOF:RIP2

GO:0006915: apoptotic process

ECO:0000314:

P

Figure 1D and Table 1.

complete
CACAO 4606


See also

References

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