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The stress-induced protein NUPR1 orchestrates protein translation during ER-stress by interacting with eIF2α

NUPR1 is a stress response protein overexpressed upon cell injury in virtually all organs including the exocrine pancreas. Despite NUPR1’s well established role in the response to cell stress, the molecular and structural machineries triggered by NUPR1 activation remain largely unknown. In this study, we uncover an important role for NUPR1 in participating in the unfolded protein response pathway and the endoplasmic reticulum stress response. Biochemical results, confirmed by ultrastructural morphological observation, revealed alterations in the UPR in acinar cells of germline-deleted NUPR1 murine models, consistent with the inability to restore general protein translation. Bioinformatical analysis of NUPR1 interacting partners showed significant enrichment in translation initiation factors, including eukaryotic initiation factor (eIF) 2α. Co-immunoprecipitation and proximity ligation assays both confirmed interaction between NUPR1 and eIF2α and its phosphorylated form (p-eIF2α). Our. Moreover, our data also suggest loss of NUPR1 in cells results in maintained eIF2α phosphorylation and evaluation of nascent proteins by (peIF2α), and click chemistry revealed that NUPR1-depleted PANC-1 cells displayed a slower post stress protein translational recovery compared to wild-type. Combined, this data proposes a novel role for NUPR1 in the integrated stress response pathway, at least partially through promoting efficient PERK-branch activity and resolution through a unique interaction with eIF2α. Significance In the pancreas, NUPR1 is required for a resolution of the ER stress response. During ER stress response, NUPR1 binds both eIF2α allowing for its dephosphorylation and restoration of new protein synthesis. Highlights Biochemical analysis revealed a general reduction in the protein expression of downstream mediators of the unfolded protein response in the pancreas of mice lacking Nupr1. This finding suggests a novel role for NUPR1 in the UPR/ER stress response. Ultrastructural analysis of pancreata revealed reduced morphological alterations in tunicamycin-treated Nupr1-/- mice compared to Nupr1+/+ mice consistent with a maintained block in general protein translation. Co-immunoprecipitation of tagged NUPR1 confirmed a novel interaction with eIF2α. Depletion of NUPR1 prolonged phosphorylation of eIF2α, suggesting it may be involved in attenuation of the PERK branch of the UPR. NUPR1-depleted PANC-1 cells displayed a slower recovery of protein translation following UPR activation