| First Author | Lee IC | Year | 2018 |
| Journal | Cell Death Differ | Volume | 25 |
| Issue | 2 | Pages | 255-267 |
| PubMed ID | 28984870 | Mgi Jnum | J:274045 |
| Mgi Id | MGI:6287168 | Doi | 10.1038/cdd.2017.152 |
| Citation | Lee IC, et al. (2018) Oxidative stress promotes SIRT1 recruitment to the GADD34/PP1alpha complex to activate its deacetylase function. Cell Death Differ 25(2):255-267 |
| abstractText | Phosphorylation of the eukaryotic translation initiation factor, eIF2alpha, 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 K(315) and K(322) with alanines or glutamines did not impair GADD34's ability to recruit protein phosphatase 1alpha (PP1alpha) or eIF2alpha, suggesting that GADD34 acetylation did not modulate eIF2alpha phosphatase activity. Arsenite (Ars)-induced oxidative stress increased cellular GADD34 levels and enhanced Sirtuin 1 (SIRT1) recruitment to assemble a cytoplasmic complex containing GADD34, PP1alpha, eIF2alpha and SIRT1. Induction of GADD34 in WT MEFs paralleled the dephosphorylation of eIF2alpha (phosphoserine-51) and SIRT1 (phosphoserine-47). By comparison, eIF2alpha and SIRT1 were persistently phosphorylated in Ars-treated GADD34-/- MEFs. Expressing WT GADD34, but not a mutant unable to bind PP1alpha in GADD34-/- MEFs restored both eIF2alpha 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-eIF2alpha levels and attenuated cell death following Ars exposure. These results highlighted a novel role for the GADD34/PP1alpha complex in coordinating the dephosphorylation and reactivation of eIF2alpha and SIRT1 to determine cell fate following oxidative stress. |
