| Autor: |
Lee, Irene Chengjie, Ho, Xue Yan, George, Simi Elizabeth, Goh, Catherine Wenhui, Sundaram, Jeyapriya Rajameenakshi, Pang, Karen Ka Lam, Luo, Weiwei, Yusoff, Permeen, Sze, Newman Siu Kwan, Shenolikar, Shirish |
| Zdroj: |
Cell Death and Differentiation; February 2018, Vol. 25 Issue: 2 p255-267, 13p |
| Abstrakt: |
Phosphorylation of the eukaryotic translation initiation factor, eIF2a, by stress-activated protein kinases and dephosphorylation by the growth arrest and DNA damage-inducible protein (GADD34)-containing phosphatase is a central node in the integrated stress response. Mass spectrometry demonstrated GADD34 acetylation at multiple lysines. Substituting K315and K322with alanines or glutamines did not impair GADD34’s ability to recruit protein phosphatase 1a (PP1a) or eIF2a, suggesting that GADD34 acetylation did not modulate eIF2a phosphatase activity. Arsenite (Ars)-induced oxidative stress increased cellular GADD34 levels and enhanced Sirtuin 1 (SIRT1) recruitment to assemble a cytoplasmic complex containing GADD34, PP1a, eIF2a and SIRT1. Induction of GADD34 in WT MEFs paralleled the dephosphorylation of eIF2a (phosphoserine-51) and SIRT1 (phosphoserine-47). By comparison, eIF2a and SIRT1 were persistently phosphorylated in Ars-treated GADD34-/- MEFs. Expressing WT GADD34, but not a mutant unable to bind PP1a in GADD34-/- MEFs restored both eIF2a and SIRT1 dephosphorylation. SIRT1 dephosphorylation increased its deacetylase activity, measured in vitro and in cells. Loss of function of GADD34 or SIRT1 enhanced cellular p-eIF2a levels and attenuated cell death following Ars exposure. These results highlighted a novel role for the GADD34/PP1a complex in coordinating the dephosphorylation and reactivation of eIF2a and SIRT1 to determine cell fate following oxidative stress. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
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