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Abrin, a Type II Ribosome Inactivating Protein: Differential Cytotoxicity and Development of the Vaccine Against its Lethality
Author(s) -
Tiwari Vinita,
Karande Anjali A
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.lb27
Subject(s) - ricin , chemistry , immunotoxin , ribosome inactivating protein , saporin , cytotoxicity , apoptosis , microbiology and biotechnology , biochemistry , ribosome , toxin , biology , in vitro , rna , gene
The plant toxin, Abrin, a type II ribosome inactivating protein, is extremely lethal, the human fatal dose being ~1 μg/kg body weight. Abrin has been classified as an agent for bioterrorism, which is of huge concern. On the other hand, the high toxic property of abrin has been employed in generating immunotoxins, where its toxin moiety is conjugated to cell surface marker specific antibodies for cell targeted killing. Different cell types exhibit variable levels of sensitivity to abrin toxicity. To gain insights into this, two cell lines requiring strikingly different IC50 of abrin for inactivating ribosomes were studied. In KB cells, the abrin A chain was found to be sequestered from the cytoplasm into the nucleus by a protein called Brain acid soluble protein (BASP‐1), enabling the cells to resist abrin‐mediated inhibition of protein synthesis. In Ovcar‐3 cells that express negligible amounts of BASP‐1, the A chain remains in the cytosol to exert its N‐glycosidase activity, therefore succumb to low concentrations of abrin. In contrast, when the apoptosis inducing activity of abrin was examined, both the cells showed comparable apoptotic population. Employing conjugates of the wild type and active site mutant ABA with the ricin B chain it was found that abrin‐induced apoptosis was dependent on inhibition of protein synthesis leading to ER‐stress in Ovcar‐3 cells, but not in KB cells. Direct DNA damage caused by the abrin A chain sequestered in the nucleus might be contributing to the apoptosis in KB cells. Towards establishing vaccines to counteract abrin‐induced lethality, we designed a recombinant chimeric protein of Abrin A chain and Abrus precatorius agglutinin A chain on the basis of epitope specificity. Abrin part of the chimera contains the epitope for the only two neutralizing antibodies; D6F10 and A7C4, reported against abrin till now. Importantly, the chimera harboured no enzymatic activity and was found to protect 100 % mice from abrin challenge upto 45 X LD 50 dose. Thus the chimera appears to be potential vaccine against abrin induced lethality. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .