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首页> 外文期刊>Cellular Physiology and Biochemistry >Inhibition of Prenylation Promotes Caspase 3 Activation, Lamin B Degradation and Loss in Metabolic Cell Viability in Pancreatic ?2-Cells
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Inhibition of Prenylation Promotes Caspase 3 Activation, Lamin B Degradation and Loss in Metabolic Cell Viability in Pancreatic ?2-Cells

机译：异戊二烯化的抑制促进了胰腺β2-细胞中胱天蛋白酶3的活化，层粘连蛋白B的降解和代谢细胞活力的丧失。

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>Background/Aims: Lamins are intermediate filament proteins that constitute the main components of the lamina underlying the inner-nuclear membrane and serve to organize chromatin. Lamins (e.g., lamin B) undergo posttranslational modifications (e.g., isoprenylation) at their C-terminal cysteine residues. Such modifications are thought to render optimal association of lamins with the nuclear envelop. Using human islets, rodent islets, and INS-1 832/13 cells, we recently reported significant metabolic defects under glucotoxic and endoplasmic reticulum (ER) stress conditions, including caspase 3 activation and lamin B degradation. The current study is aimed at further understanding the regulatory roles of protein prenylation in the induction of the aforestated metabolic defects. Methods: Subcellular phase partitioning assay was done using Triton X-114. Cell morphology and metabolic cell viability assays were carried out using standard methodologies. Results: We report that exposure of pancreatic ?2-cells to Simvastatin, an inhibitor of mevalonic acid (MVA) biosynthesis, and its downstream isoprenoid derivatives, or FTI-277, an inhibitor of farnesyltransferase that mediates farnesylation of lamins, leads to activation of caspase 3 and lamin B degradation. Furthermore, Simvastatin-treatment increased activation of p38MAPK (a stress kinase) and inhibited ERK1/2 (regulator of cell proliferation). Inhibition of farnesylation also resulted in the release of degraded lamin B into the cytosolic fraction and promoted loss in metabolic cell viability. Conclusion: Based on these findings we conclude that protein prenylation plays key roles in islet ?2-cell function. These findings affirm further support to the hypothesis that defects in prenylation pathway induce caspase-3 activation and nuclear lamin degradation in pancreatic ?2-cells under the duress of metabolic stress (e.g., glucotoxicity).
机译：> 背景/目标： 核纤层蛋白是中间的细丝蛋白，它们构成核内膜下层的主要成分并组织染色质。核纤层蛋白（例如，核纤层蛋白B）在其C端半胱氨酸残基上经历翻译后修饰（例如，异戊二烯基化）。认为这样的修饰使lamin与核被膜最佳结合。使用人类胰岛，啮齿动物的胰岛和INS-1 832/13细胞，我们最近报道了在糖毒和内质网（ER）应激条件下的重大代谢缺陷，包括caspase 3激活和层粘连蛋白B降解。目前的研究旨在进一步了解蛋白质异戊烯基化在诱导代谢缺陷中的调节作用。 方法： 使用Triton X-114进行亚细胞相分配测定。使用标准方法进行细胞形态学和代谢细胞活力测定。 结果： 我们报道了胰腺β2细胞暴露于辛伐他汀（辛伐他汀，辛伐他汀是甲羟戊酸（MVA）生物合成的抑制剂）及其下游类异戊二烯衍生物或FTI-277，法尼基转移酶抑制剂介导lamins的法尼基化，导致胱天蛋白酶3的激活和层粘连蛋白B的降解。此外，辛伐他汀治疗可增强p38MAPK（应激激酶）的激活并抑制ERK1 / 2（细胞增殖的调节剂）。法尼基化的抑制还导致降解的层粘连蛋白B释放到胞质组分中，并促进代谢细胞活力的丧失。 结论： 基于这些发现，我们得出结论，蛋白质异戊二烯基化在胰岛β2细胞功能中起关键作用。这些发现进一步证实了以下假设：异戊二烯化途径的缺陷在代谢应激（例如糖毒性）的胁迫下诱导了胰腺β2-细胞中的caspase-3活化和核纤层蛋白降解。

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