title: Inhibition of protein synthesis leading to unfolded protein response is the major event in abrin-mediated apoptosis.
abstract: Abrin obtained from the plant Abrus precatorius inhibits protein synthesis and also triggers apoptosis in cells. Previous studies from our laboratory suggested a link between these two events. Using an active site mutant of abrin A-chain which exhibits 225-fold lower protein synthesis inhibitory activity than the wild-type abrin A-chain, we demonstrate in this study that inhibition of protein synthesis induced by abrin is the major factor triggering unfolded protein response leading to apoptosis. Since abrin A-chain requires the B-chain for internalization into cells, the wild-type and mutant recombinant abrin A-chains were conjugated to native ricin B-chain to generate hybrid toxins, and the toxic effects of the two conjugates were compared. The rate of inhibition of protein synthesis mediated by the mutant ricin B-rABRA (R167L) conjugate was slower than that of the wild-type ricin B-rABRA conjugate as expected. The mutant conjugate activated p38MAPK and caspase-3 similar to its wild-type counterpart although at later time points. Overall, these results confirm that inhibition of protein synthesis is the major event contributing to abrin-mediated apoptosis.
authors.affiliation: Department of Biochemistry, Indian Institute of Science, Bangalore, 560012, Karnataka, India.
authors.forename: Ritu
authors.initials: R
authors.lastname: Mishra
authors.forename: Meenakshi Sundaram
authors.initials: MS
authors.lastname: Kumar
authors.forename: Anjali A
authors.initials: AA
authors.lastname: Karande
mesh_terms: D000036:Abrin / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002846:Chromatography, Affinity; D004705:Endocytosis / Q000187:drug effects; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D007700:Kinetics; D050505:Mutant Proteins / Q000633:toxicity; D014176:Protein Biosynthesis / Q000187:drug effects*; D017433:Protein Structure, Secondary; D012276:Ricin / Q000737:chemistry / Q000302:isolation & purification; D056811:Unfolded Protein Response / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D000036:Abrin; D012276:Ricin; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3