CYTOSKELETAL CHANGES IN HEPATOCYTES INDUCED BY MICROCYSTIS TOXINS AND THEIR RELATION TO HYPERPHOSPHORYLATION OF CELL-PROTEINS
CYTOSKELETAL CHANGES IN HEPATOCYTES INDUCED BY MICROCYSTIS TOXINS AND THEIR RELATION TO HYPERPHOSPHORYLATION OF CELL-PROTEINS
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DOI：
10.1016/0009-2797(92)90033-h
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发表时间：
1992-01-01
影响因子：
5.1
通讯作者：
YEUNG, DSK
中科院分区：
文献类型：
--
作者：
FALCONER, IR;YEUNG, DSK
铜绿微囊藻（Microcystis aeruginosa）产生的七肽毒素对哺乳动物具有选择性肝毒性。肝脏的特征性死后病理学是由于窦破裂、血液渗漏到组织中和肝细胞崩解导致的广泛小叶破裂。用毒素孵育的分离肝细胞显示严重的结构畸形和表面起泡。本文阐述了微囊藻毒素对肌动蛋白微丝的收缩和聚集，以及对细胞角蛋白中间丝的迁移和分解，在培养的肝细胞的影响。早期的工作没有显示肌动蛋白的组装/拆卸的变化，然而，本文证明了细胞角蛋白的变化，从中间丝分布在毒素影响的细胞的细胞质中的颗粒。从肝细胞的细胞骨架组分的丙烯酰胺凝胶电泳没有显示总的细胞角蛋白的变化，但是，在52和58 kDa的细胞角蛋白的免疫原性的显着变化被视为毒素暴露的细胞。与对照孵育相比，用[P-32]正磷酸盐孵育的毒素影响的细胞中蛋白质的P-32磷酸化的测量显示出显著增加。这与其他地方描述微囊藻毒素体外抑制磷酸酶的研究一致。这些数据表明，磷酸化的细胞角蛋白是毒素暴露于肝细胞后胞质部分磷酸化蛋白的主要成分。结论：微囊藻对肝细胞的毒性机制是通过细胞骨架的破坏导致细胞形态的丧失、细胞与细胞的粘附，最终导致细胞坏死。潜在的生化病变可能是磷酸酶抑制，导致许多肝细胞蛋白过度磷酸化，包括负责微丝方向和中间丝完整性的细胞角蛋白。
The heptapeptide toxins produced by the blue-green alga (cyanobacterium) Microcystis aeruginosa are selectively hepatotoxic in mammals. The characteristic post-mortem pathology of the liver is extensive lobular disruption due to sinusoidal breakdown, leakage of blood into the tissue and hepatocyte disintegration. Isolated hepatocytes incubated with toxin show severe structural deformity and surface blebbing. This paper demonstrates the effects of Microcystis toxins on the contraction and aggregation of actin microfilaments, and on the relocation and breakdown of cytokeratin intermediate filaments, in cultured hepatocytes. Earlier work did not show changes in the assembly/disassembly of actin; however, this paper demonstrates the change in cytokeratin from intermediate filaments to distributed granules in the cytoplasm of toxin-affected cells. Acrylamide gel electrophoresis of cytoskeletal fractions from hepatocytes did not show changes in total cytokeratins; however, marked changes in the immunogenicity of cytokeratins at 52 and 58 kDa were seen on toxin exposure of cells. Measurement of P-32-phosphorylation of proteins in toxin-affected cells incubated with [P-32]orthophosphate showed a dramatic increase compared to control incubations. This is in agreement with research elsewhere describing phosphatase inhibition in vitro by Microcystis toxins. The data indicate that phosphorylated cytokeratin is a major component of cytoplasmic fraction phosphorylated protein after toxin exposure to hepatocytes. It is concluded that the mechanism of Microcystis toxicity to the hepatocyte is through cytoskeletal damage leading to loss of cell morphology, cell to cell adhesion and finally cellular necrosis. The underlying biochemical lesion is likely to be phosphatase inhibition causing hyperphosphorylation of a number of hepatocyte proteins, including those cytokeratins responsible for microfilament orientation and intermediate filament integrity.