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

Abstract

NUPR1 is an 82 amino-acids 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. Here we report that NUPR1 plays a central role during the endoplasmic reticulum stress response. Biochemical analysis revealed a general attenuation of the unfolded protein response in pancreas of mice lacking NUPR1. Ultrastructural analysis of pancreata revealed fewer morphological alteration in tunicamycin-treated Nupr1 -/compared to Nupr1 +/+ . A bioinformatical analysis of potential interacting partners of NUPR1 showed significant enrichment in translation initiation factors, including eIF2α. Co-immunoprecipitation of tagged NUPR1 confirmed that the protein binds to both eIF2α and its phosphorylated form (p-eIF2α). Depletion of NUPR1 lead to prolonged phosphorylation of eIF2α. Finally, click chemistry revealed NUPR1-depleted Panc-1 cells displayed a decrease in the amount of nascent proteins in response to ER stress induction compared to wild-type cells. Thus, NUPR1 is necessary for an efficient PERK-branch activation by binding to the p-eIF2α and, consequently, promoting protein synthesis during the ER stress response.