A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress.
A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress.
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发表时间：
2005
期刊：
影响因子：
56.9
通讯作者：
M. Boyce;Kevin F. Bryant;C. Jousse;K. Long;H. Harding;D. Scheuner;R. Kaufman;D. Ma;D. Coen
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文献类型：
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作者：
M. Boyce;Kevin F. Bryant;C. Jousse;K. Long;H. Harding;D. Scheuner;R. Kaufman;D. Ma;D. Coen
大多数蛋白磷酸酶几乎没有固有的底物专一性，这使得选择性的药物抑制特定的去磷酸化反应成为一个具有挑战性的问题。在筛选保护细胞免受内质网(ER)应激的小分子时，我们确定了salubrine，一种选择性抑制真核细胞翻译起始因子2亚单位α(EIF2pha)去磷酸化的细胞复合体。Salubrine还阻止由单纯疱疹病毒蛋白介导的eIF2pha去磷酸化，并抑制病毒复制。这些结果表明，eIF2α去磷酸化的选择性化学抑制剂可能在涉及内质网应激或病毒感染的疾病中有用。更广泛地说，salubrine证明了选择性药物靶向细胞去磷酸化事件的可行性。
Most protein phosphatases have little intrinsic substrate specificity, making selective pharmacological inhibition of specific dephosphorylation reactions a challenging problem. In a screen for small molecules that protect cells from endoplasmic reticulum (ER) stress, we identified salubrinal, a selective inhibitor of cellular complexes that dephosphorylate eukaryotic translation initiation factor 2 subunit alpha (eIF2alpha). Salubrinal also blocks eIF2alpha dephosphorylation mediated by a herpes simplex virus protein and inhibits viral replication. These results suggest that selective chemical inhibitors of eIF2alpha dephosphorylation may be useful in diseases involving ER stress or viral infection. More broadly, salubrinal demonstrates the feasibility of selective pharmacological targeting of cellular dephosphorylation events.