CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum
CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum
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DOI：
10.1101/gad.1250704
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发表时间：
2004-12-15
影响因子：
10.5
通讯作者：
Ron, D
中科院分区：
文献类型：
--
作者：
Marciniak, SJ;Yun, CY;Ron, D
未折叠和折叠错误的客户蛋白对内质网（ER）施加压力，在病理生理条件下导致细胞死亡。转录因子C/EBP同源蛋白（CHOP）可被内质网应激激活，CHOP的缺失可预防其致命后果。我们发现CHOP直接激活GADD34， GADD34在应激细胞中通过去磷酸化翻译起始因子2 (eIF2alpha) α亚基磷酸丝氨酸51来促进内质网客户蛋白的生物合成。因此，GADD34表达受损降低了暴露于内质网功能受损扰动的CHOP-/-细胞的客户蛋白负荷和内质网应激。CHOP-/-和GADD34突变细胞在应激内质网中积累的高分子量蛋白复合物比野生型细胞少。此外，缺乏gadd34导向的eIF2alpha去磷酸化的小鼠，如CHOP-/-小鼠，对内质网应激诱导药物tunicamycin的肾毒性具有抗性。CHOP还能激活编码内质网氧化酶的ero1 α。因此，应激CHOP-/-细胞的内质网是相对低氧化的。促进低氧化内质网的药理学和遗传学操作可减少应激内质网中异常的高分子量蛋白复合物，并保护内质网免受应激的致命后果。因此，CHOP缺失通过减少内质网客户蛋白负荷和改变细胞器内的氧化还原条件来保护细胞免受内质网应激。
Unfolded and malfolded client proteins impose a stress on the endoplasmic reticulum (ER), which contributes to cell death in pathophysiological conditions. The transcription factor C/EBP homologous protein (CHOP) is activated by ER stress, and CHOP deletion protects against its lethal consequences. We find that CHOP directly activates GADD34, which promotes ER client protein biosynthesis by dephosphorylating phospho-Ser 51 of the alpha-subunit of translation initiation factor 2 (eIF2alpha) in stressed cells. Thus, impaired GADD34 expression reduces client protein load and ER stress in CHOP-/- cells exposed to perturbations that impair ER function. CHOP-/- and GADD34 mutant cells accumulate less high molecular weight protein complexes in their stressed ER than wild-type cells. Furthermore, mice lacking GADD34-directed eIF2alpha dephosphorylation, like CHOP-/- mice, are resistant to renal toxicity of the ER stress-inducing drug tunicamycin. CHOP also activates ERO1alpha, which encodes an ER oxidase. Consequently, the ER of stressed CHOP-/- cells is relatively hypo-oxidizing. Pharmacological and genetic manipulations that promote a hypo-oxidizing ER reduce abnormal high molecular weight protein complexes in the stressed ER and protect from the lethal consequences of ER stress. CHOP deletion thus protects cells from ER stress by decreasing ER client protein load and changing redox conditions within the organelle.