GCN2 phosphorylation of eIF2α activates NF-κB in response to UV irradiation
GCN2 phosphorylation of eIF2α activates NF-κB in response to UV irradiation
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DOI：
10.1042/bj20041164
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发表时间：
2005-01-15
影响因子：
4.1
通讯作者：
Wek, RC
中科院分区：
文献类型：
--
作者：
Jiang, HY;Wek, RC
为了响应紫外线照射，哺乳动物细胞引发基因表达程序，旨在修复损伤并控制细胞增殖和凋亡。这种应激反应的重要成员包括NF-κ B（核因子-κ B）家族。然而，紫外线照射激活NF-κ B的机制还不清楚。在真核生物中，各种环境压力被一个蛋白激酶家族识别和修复，该蛋白激酶家族磷酸化eIF 2（真核起始因子-2）的α亚基。在本研究中，我们表明，NF-κ B在MEF（鼠胚胎成纤维细胞）细胞被激活的UV-C和UV-B辐射通过一种机制，需要eIF 2 α磷酸化。响应UV的主要eIF 2 α激酶是GCN 2（一般对照非去阻遏-2），PEK/PERK（胰腺eIF 2 α激酶/RNA依赖性蛋白激酶样内质网激酶）执行次要功能。我们的研究表明，降低蛋白质合成伴随eIF 2 α磷酸化，结合eIF 2a激酶非依赖性周转的IkappaB α（kappaB α的抑制剂），降低水平的IkappaB α在响应紫外线照射。从抑制性IkappaB α释放NF-κ B将促进NF-κ B进入细胞核和靶向转录控制。我们还发现，MEF细胞中GCN 2的缺失显著增强了对UV暴露的响应，类似于在NF-κ B的RelA/p65亚基缺失的细胞中测量的凋亡。这些结果表明，GCN 2是中央识别紫外线应激，和eIF 2 α磷酸化提供抗细胞凋亡响应这种环境的侮辱。
In response to UV irradiation, mammalian cells elicit a gene expression programme designed to repair damage and control cell proliferation and apoptosis. Important members of this stress response include the NF-kappaB (nuclear factor-kappaB) family. However, the mechanisms by which UV irradiation activates NF-kappaB are not well understood. In eukaryotes, a variety of environmental stresses are recognized and remediated by a family of protein kinases, that phosphorylate the alpha subunit of eIF2 (eukaryotic initiation factor-2). In the present study we show that NF-kappaB in MEF (murine embryo fibroblast) cells is activated by UV-C and UV-B irradiation through a mechanism requiring eIF2alpha phosphorylation. The primary eIF2alpha kinase in response to UV is GCN2 (general control non-derepressible-2), with PEK/PERK (pancreatic eIF2alpha kinase/RNA-dependent-protein-kinase-like endoplasmic-reticulum kinase) carrying out a secondary function. Our studies indicate that lowered protein synthesis accompanying eIF2alpha phosphorylation, combined with eIF2a kinase-independent turnover of IkappaBalpha (inhibitor of kappaBalpha), reduces the levels of IkappaBalpha in response to UV irradiation. Release of NF-kappaB from the inhibitory IkappaBalpha would facilitate NF-kappaB entry into the nucleus and targeted transcriptional control. We also find that loss of GCN2 in MEF cells significantly enhances apoptosis in response to UV exposure similar to that measured in cells deleted for the RelA/p65 subunit of NF-kappaB. These results demonstrate that GCN2 is central to recognition of UV stress, and that eIF2alpha phosphorylation provides resistance to apoptosis in response to this environmental insult.