Department of Biochemistry, Indian Institute of Science, Bangalore, Karnataka, India.
IUBMB Life. 2019 Mar;71(3):357-363. doi: 10.1002/iub.1980. Epub 2018 Dec 2.
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 concern. Conversely, the high toxic property of abrin has been employed in generating immunotoxins, whereas 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; therefore, adequate knowledge of the molecular mechanism that governs the activity of the protein would be a safeguard. To gain insights into this, two cell lines requiring strikingly different concentrations of abrin for inactivating ribosomes were studied. Employing conjugates of the wild-type and active site mutant of abrin A chain with the ricin B chain, it was found that abrin-induced apoptosis was dependent on inhibition of protein synthesis (PSI) leading to ER-stress in Ovcar-3 cells, but not in KB cells. Abrin was also observed to cause direct DNA damage in KB cells, while in Ovcar-3 cells abrin-induced DNA damage was found to be dependent on caspases. Overall, the study demonstrates that the correlation of abrin-mediated PSI and apoptosis is cell-specific and abrin can induce more than one pathway to cause cell death. © 2018 IUBMB Life, 71(3):357-363, 2019.
植物毒素相思豆毒素 A，一种 II 型核糖体失活蛋白，毒性极强，人类的致命剂量约为 1μg/kg 体重。相思豆毒素已被归类为生物恐怖主义制剂，这令人担忧。相反，相思豆毒素的高毒性已被用于生成免疫毒素，其毒素部分与细胞表面标记物特异性抗体结合，用于靶向细胞杀伤。不同的细胞类型对相思豆毒素的毒性表现出不同的敏感性；因此，充分了解控制该蛋白活性的分子机制将是一种保障。为了深入了解这一点，研究了两种需要截然不同浓度的相思豆毒素才能使核糖体失活的细胞系。使用相思豆毒素 A 链的野生型和活性位点突变体与蓖麻毒素 B 链的缀合物，发现相思豆毒素诱导的细胞凋亡依赖于抑制蛋白合成（PSI），导致 Ovcar-3 细胞内质网应激，但不依赖于 KB 细胞。还观察到相思豆毒素直接在 KB 细胞中引起 DNA 损伤，而在 Ovcar-3 细胞中，发现相思豆毒素诱导的 DNA 损伤依赖于半胱天冬酶。总的来说，该研究表明，相思豆毒素介导的 PSI 和凋亡的相关性是细胞特异性的，并且相思豆毒素可以诱导多种途径导致细胞死亡。
