SIRT1 与 eIF2-α 结合并调节细胞应激反应。

SIRT1 associates with eIF2-alpha and regulates the cellular stress response.

机构信息

Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA; Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.

出版信息

Sci Rep. 2011;1:150. doi: 10.1038/srep00150. Epub 2011 Nov 9.

SIRT1 is a NAD+ dependent protein deacetylase known to increase longevity in model organisms. SIRT1 regulates cellular response to oxidative and/or genotoxic stress by regulating proteins such as p53 and FOXO. The eukaryotic initiation factor-2, eIF2, plays a critical role in the integrated stress response pathway. Under cellular stress, phosphorylation of the alpha subunit of eIF2 is essential for immediate shut-off of translation and activation of stress response genes. Here we demonstrate that SIRT1 interacts with eIF2α. Loss of SIRT1 results in increased phosphorylation of eIF2α. However, the downstream stress induced signaling pathway is compromised in SIRT1-deficient cells, indicated by delayed expression of the downstream target genes CHOP and GADD34 and a slower post-stress translation recovery. Finally, SIRT1 co-immunoprecipitates with mediators of eIF2α dephosphorylation, GADD34 and CreP, suggesting a role for SIRT1 in the negative feedback regulation of eIF2α phosphorylation.

SIRT1 是一种依赖 NAD+的蛋白去乙酰化酶，已知它可以延长模型生物的寿命。SIRT1 通过调节 p53 和 FOXO 等蛋白质来调节细胞对氧化和/或遗传毒性应激的反应。真核起始因子 2（eIF2）在综合应激反应途径中起着关键作用。在细胞应激下，eIF2α 的α亚基磷酸化对于立即关闭翻译和激活应激反应基因是必不可少的。在这里，我们证明 SIRT1 与 eIF2α 相互作用。SIRT1 的缺失会导致 eIF2α 的磷酸化增加。然而，SIRT1 缺陷细胞中的下游应激诱导信号通路受损，表现为下游靶基因 CHOP 和 GADD34 的表达延迟，以及应激后翻译恢复较慢。最后，SIRT1 与 eIF2α 去磷酸化的介质 GADD34 和 CreP 共同免疫沉淀，表明 SIRT1 在 eIF2α 磷酸化的负反馈调节中起作用。