ERdj5 sensitizes neuroblastoma cells to ER stress-induced apoptosis via regulation of eLF2a signaling Free

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The accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER) (ER stress) induces a coordinated adaptive program called the unfolded protein response (UPR). The UPR alleviates stress by upregulating protein folding and degradation pathways and inhibiting protein synthesis. Translational repression is mediated by increased phosphorylation of eukaryotic translation initiation factor 2a (eIF2a). Although the activation of the UPR normally succeeds in restoring ER homeostasis, persistent or intense ER stress can trigger apoptosis. Here we demonstrate that the Thioredoxin domains-containing novel ER-resident chaperone molecule ERdj5 affects cell survival and controls eIF2a phosphorylation and signaling in response to ER stress. We show that overexpression of ERdj5 induces both G₁/S cell cycle arrest and apoptosis in neuroblastoma cells in response to ER stress. ERdj5 overexpression delays the eIF2a dephosphorylation and the translational recovery normally observed late in the stress response by decreasing the expression of GADD34, a subunit of the PP1-holophosphatase complex that dephosphorylates eIF2a when the stress is overcome. Furthermore, defective recovery of protein synthesis impairs translation of stress-induced proteins in the ERdj5-overexpressing cells. These observations indicate that ERdj5-mediated delay of translational recovery decreases cancer cell resistance to apoptosis induced by ER stress.