Evaluation of the endoplasmic reticulum-stress response in eIF2B-mutated lymphocytes and lymphoblasts from CACH/VWM patients.
Evaluation of the endoplasmic reticulum-stress response in eIF2B-mutated lymphocytes and lymphoblasts from CACH/VWM patients.
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DOI：
10.1186/1471-2377-10-94
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发表时间：
2010-10-19
期刊：
影响因子：
2.6
通讯作者：
Fogli A
中科院分区：
文献类型：
--
作者：
Horzinski L;Kantor L;Huyghe A;Schiffmann R;Elroy-Stein O;Boespflug-Tanguy O;Fogli A
真核翻译起始因子2B（eIF 2B）是一种鸟嘌呤核苷酸交换因子（GEF），是正常和应激条件下翻译起始的关键调节因子，可引起广泛的常染色体隐性脑白质营养不良。来自eIF 2B突变患者的EBV永生化淋巴细胞（EIL）表现出eIF 2B GEF活性降低。eIF 2B突变的原代成纤维细胞具有转录激活因子4（ATF 4）的超诱导，其参与保护性未折叠蛋白反应（UPR），也称为ER应激反应。我们检验了来自eIF 2B突变患者的EIL也表现出增强的ER应激反应的假设。我们使用毒胡萝卜素作为ER应激剂，并观察了正常和eIF 2B突变的EIL中的多聚体概况、蛋白质合成速率、ATF 4的翻译激活以及应激特异性mRNA（ATF 4、CHOP、ASNS、GRP 78）的转录诱导。我们还比较了EIL和原代淋巴细胞（PL）之间的应激特异性mRNA水平。尽管在测试的12种eIF 2B突变的EIL细胞系中eIF 2B GEF活性较低（范围为正常的40-70%），但这些细胞系在其ATF 4介导的ER应激反应方面与正常EIL没有差异。与原代成纤维细胞相比，eIF 2B突变的EIL中不存在ATF 4介导的ER应激反应的过度诱导，这与它们被EB病毒转化无关。事实上，与EIL相比，PL表现出更高的应激特异性mRNA的诱导，但与对照相比，在eIF 2B突变的细胞系中没有观察到UPR的过度诱导。结合其他人的工作，我们的结果表明对照细胞和eIF 2B突变细胞之间的ER应激反应不存在重大差异。因此，ER应激反应的组分不能用作eIF 2B相关疾病的判别标志物。
Eukaryotic translation initiation factor 2B (eIF2B), a guanine nucleotide exchange factor (GEF) and a key regulator of translation initiation under normal and stress conditions, causes an autosomal recessive leukodystrophy of a wide clinical spectrum. EBV-immortalised lymphocytes (EIL) from eIF2B-mutated patients exhibit a decrease in eIF2B GEF activity. eIF2B-mutated primary fibroblasts have a hyper-induction of activating transcription factor 4 (ATF4) which is involved in the protective unfolded protein response (UPR), also known as the ER-stress response. We tested the hypothesis that EIL from eIF2B-mutated patients also exhibit a heightened ER-stress response. We used thapsigargin as an ER-stress agent and looked at polysomal profiles, rate of protein synthesis, translational activation of ATF4, and transcriptional induction of stress-specific mRNAs (ATF4, CHOP, ASNS, GRP78) in normal and eIF2B-mutated EIL. We also compared the level of stress-specific mRNAs between EIL and primary lymphocytes (PL). Despite the low eIF2B GEF activity in the 12 eIF2B-mutated EIL cell lines tested (range 40-70% of normal), these cell lines did not differ from normal EIL in their ATF4-mediated ER-stress response. The absence of hyper-induction of ATF4-mediated ER-stress response in eIF2B-mutated EIL in contrast to primary fibroblasts is not related to their transformation by EBV. Indeed, PL exhibited a higher induction of the stress-specific mRNAs in comparison to EIL, but no hyper-induction of the UPR was noticed in the eIF2B-mutated cell lines in comparison to controls. Taken together with work of others, our results demonstrate the absence of a major difference in ER-stress response between controls and eIF2B-mutated cells. Therefore, components of the ER-stress response cannot be used as discriminantory markers in eIF2B-related disorders.
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影响因子：
3.7
作者：
Kantor L;Pinchasi D;Mintz M;Hathout Y;Vanderver A;Elroy-Stein O
通讯作者：
Elroy-Stein O
影响因子：
3.7
作者：
Horzinski L;Huyghe A;Cardoso MC;Gonthier C;Ouchchane L;Schiffmann R;Blanc P;Boespflug-Tanguy O;Fogli A
通讯作者：
Fogli A
DOI：
10.1097/01.jnen.0000228201.27539.50
发表时间：
2006-07-01
影响因子：
3.2
作者：
van Kollenburg, Barbara;van Dijk, Jantine;van der Knaap, Marjo S.
通讯作者：
van der Knaap, Marjo S.
影响因子：
82.9
作者：
Dietrich, J;Lacagnina, M;Pröschel, C
通讯作者：
Pröschel, C
影响因子：
3.9
作者：
Fogli, A;Boespflug-Tanguy, O
通讯作者：
Boespflug-Tanguy, O