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首页> 外文期刊>Molecular and Cellular Biology >Control of Cellular GADD34 Levels by the 26S Proteasome
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Control of Cellular GADD34 Levels by the 26S Proteasome

机译：26S蛋白酶体对细胞GADD34水平的控制

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GADD34, the product of a growth arrest and DNA damage-inducible gene, is expressed at low levels in unstressed cells. In response to stress, the cellular content of GADD34 protein increases and, on termination of stress, rapidly declines. We investigated the mechanisms that control GADD34 levels in human cells. GADD34 proteins containing either an internal FLAG or a C-terminal green fluorescent protein epitope were degraded at rates similar to endogenous GADD34. However, the addition of epitopes at the N terminus or deletion of N-terminal sequences stabilized GADD34. N-terminal peptides of GADD34, either alone or fused to heterologous proteins, exhibited rapid degradation similar to wild-type GADD34, thereby identifying an N-terminal degron. Deletion of internal PEST repeats had no impact on GADD34 stability but modulated the binding and activity of protein phosphatase 1. Proteasomal but not lysosomal inhibitors enhanced GADD34 stability and eukaryotic initiation factor 2α (eIF-2α) dephosphorylation, a finding consistent with GADD34's role in assembling an eIF-2α phosphatase. GADD34 was polyubiquitinated, and this modification enhanced its turnover in cells. A stabilized form of GADD34 promoted the accumulation and aggregation of the mutant cystic fibrosis transmembrane conductance regulator (CFTRΔF508), highlighting the physiological importance of GADD34 turnover in protein processing in the endoplasmic reticulum and the potential impact of prolonged GADD34 expression in human disease.
机译：GADD34是生长停滞和DNA损伤诱导基因的产物，在未受压力的细胞中低水平表达。响应压力，GADD34蛋白的细胞含量增加，并且在压力终止时迅速下降。我们研究了控制人类细胞中GADD34水平的机制。含有内部FLAG或C端绿色荧光蛋白表位的GADD34蛋白以类似于内源GADD34的速率降解。但是，在N末端添加表位或删除N末端序列可稳定GADD34。单独或与异源蛋白融合的GADD34的N末端肽表现出与野生型GADD34相似的快速降解，从而鉴定出N末端的降解子。内部PEST重复序列的缺失对GADD34的稳定性没有影响，但调节了蛋白磷酸酶1的结合和活性。蛋白酶体而不是溶酶体抑制剂增强了GADD34的稳定性和真核起始因子2α（eIF-2α）的去磷酸化，这一发现与GADD34在组装中的作用一致eIF-2α磷酸酶。 GADD34被多泛素化，这种修饰增加了其在细胞中的更新。稳定形式的GADD34促进了突变型囊性纤维化跨膜电导调节剂（CFTRΔF508）的积累和聚集，突显了GADD34周转率在内质网中蛋白质加工中的生理重要性以及GADD34延长表达在人类疾病中的潜在影响。

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