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首页> 外文期刊>American Journal of Physiology >Targeting of the molecular chaperone oxygen-regulated protein 150 (ORP150) to mitochondria and its induction by cellular stress
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Targeting of the molecular chaperone oxygen-regulated protein 150 (ORP150) to mitochondria and its induction by cellular stress

机译：分子伴侣氧调节蛋白150（ORP150）靶向线粒体及其细胞应激诱导

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First published December 19, 2007; doi:10.1152/ajpcell.00400.2007.-Oxygen-regulated protein 150 (ORP150) is an inducible endoplasmic reticulum (ER) chaperone molecule that is upregulated after numerous cellular insults and has a cytoprotective role in renal, neural, and cardiac models of ischemia-reperfusion injury. ORP150 also has been shown to play a role in cellular Ca~(2+) homeostasis, and in turn, regulating calpain activity. In this study, we identified ORP150 in whole rat renal cortical mitochondria and matrix fractions, demonstrated the targeting of an ORP150-GFP construct to the mitochondria of NIH-3T3 cells, and showed that the NH2-terminal 13 amino acids of ORP150 are sufficient for this translocation. ORP150 expression was found to be regulated by the anti-C/enhancer-binding protein homologous protein (CHOP)/ GADD153 transcription factor and ORP150 levels increased in the mitochondria and ER of COS-7 cells after diverse stresses, including hypoxia, serum starvation, prolyl hydroxylase inhibition with dimethyloxaloylglycine, and exposure to tunicamycin, ethidium, bromide, and 2-deoxyglucose. Induction of the mitochondrial specific stress response in COS-7 cells through expression of an ornithine transcarbamylase mutant (AOTC) increased mitochondrial ORP150 levels and mitochondrial calpain activity. To determine whether mitochondrial ORP150 and mitochondrial calpain 10 interact, rat cortical mitochondria exposed to Ca~(2+) resulted in ORP150 cleavage in a calpain inhibitor-dependent manner, revealing that ORP150 is a substrate and may be regulated by caipain 10. These data reveal a novel cellular localization for ORP150 and that mitochondrial ORP150 is upregulated by CHOP/GADD153 in response to mitochondrial and ER stress. Our data also reveal that ORP150 is a substrate for mitochondrial calpain 10.
机译：首次发布于2007年12月19日; doi：10.1152 / ajpcell.00400.2007.-氧气调节蛋白150（ORP150）是一种可诱导的内质网（ER）伴侣分子，在多次细胞损伤后均被上调，并且在缺血，肾脏和神经系统心脏模型中具有细胞保护作用再灌注损伤。 ORP150还被证明在细胞Ca〜（2+）稳态中起着一定的作用，进而调节钙蛋白酶的活性。在这项研究中，我们在整个大鼠肾皮质线粒体和基质组分中鉴定了ORP150，证明了ORP150-GFP构建体靶向NIH-3T3细胞的线粒体，并表明ORP150的NH2末端13个氨基酸足以这种易位。发现ORP150的表达受抗C /增强子结合蛋白同源蛋白（CHOP）/ GADD153转录因子的调节，并且在多种应激（包括缺氧，血清饥饿，用二甲基草酰甘氨酸抑制脯氨酰羟化酶，并暴露于衣霉素，乙锭，溴化物和2-脱氧葡萄糖。通过表达鸟氨酸转氨甲酰酶突变体（AOTC）诱导COS-7细胞中的线粒体比应激反应增加了线粒体ORP150水平和线粒体钙蛋白酶活性。为了确定线粒体ORP150和线粒体钙蛋白酶10是否相互作用，暴露于Ca〜（2+）的大鼠皮质线粒体以钙蛋白酶抑制剂依赖性方式导致ORP150裂解，表明ORP150是底物，并且可能受到caipain 10的调节。这些数据揭示了ORP150的新型细胞定位，线粒体ORP150被CHOP / GADD153上调以响应线粒体和ER应激。我们的数据还显示，ORP150是线粒体钙蛋白酶10的底物。

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