Inhibition of a constitutive translation initiation factor 2alpha phosphatase, CReP, promotes survival of stressed cells.
Inhibition of a constitutive translation initiation factor 2alpha phosphatase, CReP, promotes survival of stressed cells.
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DOI：
10.1083/jcb.200308075
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发表时间：
2003-11-24
期刊：
影响因子：
--
通讯作者：
Ron D
中科院分区：
文献类型：
--
作者：
Jousse C;Oyadomari S;Novoa I;Lu P;Zhang Y;Harding HP;Ron D
真核生物翻译起始因子2α（eIF 2 α）丝氨酸51位的磷酸化受特异性应激激活蛋白激酶的影响。eIF 2 α磷酸化抑制翻译起始，促进称为整合应激反应（ISR）的细胞保护基因表达程序。应激诱导的GADD 34激活通过促进eIF 2 α去磷酸化对该途径产生负反馈，然而，GADD 34突变体细胞保留了显著的eIF 2 α定向磷酸酶活性。我们使用体细胞遗传学方法鉴定了编码组成型活性全磷酸酶复合物的新型调节亚基的基因，该复合物可使eIF 2 α去磷酸化。该基因被我们命名为eIF 2 α磷酸化组成型阻遏物（constitutive repressor of eIF 2 α phosphorylation，CReP，或PPP 1 R15 B），通过RNAi抑制eIF 2 α磷酸化组成型阻遏物的活性，激活ISR。CReP RNAi强烈地保护哺乳动物细胞免受氧化应激、过氧亚硝酸盐应激，并且更适度地防止错误折叠蛋白质在内质网中的积累。这些发现表明，通过靶向CReP-蛋白-磷酸酶-1复合物来治疗性抑制eIF 2 α去磷酸化可用于获得ISR的有益质量。
Phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) on serine 51 is effected by specific stress-activated protein kinases. eIF2α phosphorylation inhibits translation initiation promoting a cytoprotective gene expression program known as the integrated stress response (ISR). Stress-induced activation of GADD34 feeds back negatively on this pathway by promoting eIF2α dephosphorylation, however, GADD34 mutant cells retain significant eIF2α-directed phosphatase activity. We used a somatic cell genetic approach to identify a gene encoding a novel regulatory subunit of a constitutively active holophosphatase complex that dephosphorylates eIF2α. RNAi of this gene, which we named constitutive repressor of eIF2α phosphorylation (CReP, or PPP1R15B), repressed the constitutive eIF2α-directed phosphatase activity and activated the ISR. CReP RNAi strongly protected mammalian cells against oxidative stress, peroxynitrite stress, and more modestly against accumulation of malfolded proteins in the endoplasmic reticulum. These findings suggest that therapeutic inhibition of eIF2α dephosphorylation by targeting the CReP-protein–phosphatase-1 complex may be used to access the salubrious qualities of the ISR.
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影响因子：
16
作者：
Harding, HP;Zhang, YH;Ron, D
通讯作者：
Ron, D
DOI：
10.1101/sqb.2001.66.499
发表时间：
2001-01-01
期刊：
COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY
影响因子：
--
作者：
Harding, HP;Novoa, I;Ron, D
通讯作者：
Ron, D
影响因子：
16
作者：
Harding, HP;Novoa, I;Ron, D
通讯作者：
Ron, D
影响因子：
5.6
作者：
Ma, YJ;Brewer, JW;Hendershot, LM
通讯作者：
Hendershot, LM
影响因子：
5.3
作者：
Brush, MH;Weiser, DC;Shenolikar, S
通讯作者：
Shenolikar, S