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首页> 外文期刊>American Journal of Physiology >Alterations in molecular chaperones and eIF2alpha during lung endothelial cell apoptosis.
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Alterations in molecular chaperones and eIF2alpha during lung endothelial cell apoptosis.

机译：肺血管内皮细胞凋亡过程中分子伴侣和eIF2alpha的变化。

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We have previously demonstrated that inhibition of CAAX carboxyl methylation with AGGC caused redistribution and condensation of the ER molecular chaperones, glucose-regulated protein (GRP)-94 and calnexin; an effect that was attenuated by overexpression of dominant active RhoA. We have also shown that AGGC decreased GRP94 protein level; an effect that was dependent on caspase activity. In the present study, we tested the effects of inhibition of posttranslational processing of CAAX proteins on localization and protein levels of molecular chaperones and phosphorylation and protein level of eIF2alpha. We found that both AGGC, which inhibits CAAX carboxyl methylation, and simvastatin, which inhibits CAAX geranylgeranylation, caused relocalization of GRP94, calnexin, and calreticulin, effects that were not seen during endothelial apoptosis induced by TNF-alpha or ultraviolet (UV) irradiation. These results suggest that posttranslational processing of CAAX proteins is important in maintaining localization of molecular chaperones normally found in the ER. We also noted that AGGC, but not simvastatin, TNF-alpha, or UV irradiation, decreased protein levels of most molecular chaperones. Increased eIF2alpha phosphorylation was observed in the early stages of apoptosis, which was independent of the cause of apoptosis. These results suggest that eIF2alpha phosphorylation is a common early response to apoptosis-inducing stimuli. Interestingly, eIF2alpha protein level was decreased in the late stages of apoptosis induced by AGGC, TNF-alpha, and UV irradiation: an effect that was prevented by caspase inhibition. Thus we speculate that caspase(s)-dependent proteolysis of molecular chaperones and eIF2alpha may be novel signaling pathways of apoptosis. We also speculate that increased eIF2alpha phosphorylation is a defensive response against endothelial cell apoptosis.
机译：先前我们已经证明，AGGC抑制CAAX羧基甲基化会导致ER分子伴侣，葡萄糖调节蛋白（GRP）-94和钙联接蛋白的重新分布和缩合。显性活性RhoA的过表达减弱了这种作用。我们还显示了AGGC降低了GRP94蛋白质水平。取决于胱天蛋白酶活性的作用。在本研究中，我们测试了CAAX蛋白翻译后加工的抑制作用对分子伴侣蛋白的定位和蛋白水平以及eIF2alpha的磷酸化和蛋白水平的影响。我们发现，AGGC（抑制CAAX羧基甲基化）和辛伐他汀（抑制CAAX香叶基香叶基化）均引起GRP94，钙粘蛋白和钙网蛋白的重新定位，这在TNF-α或紫外线（UV）辐射诱导的内皮细胞凋亡过程中未见到。这些结果表明，CAAX蛋白的翻译后加工对于维持通常在ER中发现的分子伴侣的定位很重要。我们还注意到，AGGC降低了大多数分子伴侣的蛋白质水平，但没有使辛伐他汀，TNF-α或紫外线辐射降低。在细胞凋亡的早期阶段观察到eIF2alpha磷酸化增加，这与细胞凋亡的原因无关。这些结果表明eIF2alpha磷酸化是常见的早期反应，诱导细胞凋亡。有趣的是，在AGGC，TNF-α和UV辐射诱导的凋亡晚期，eIF2alpha蛋白水平降低：这种作用被半胱天冬酶抑制所阻止。因此，我们推测分子伴侣和eIF2alpha的caspase依赖性蛋白水解可能是细胞凋亡的新信号通路。我们还推测增加的eIF2alpha磷酸化是对内皮细胞凋亡的防御反应。

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