期刊
FEBS JOURNAL
卷 288, 期 13, 页码 4081-4097出版社
WILEY
DOI: 10.1111/febs.15700
关键词
eIF2 alpha; ER stress; NUPR1; protein translation; unfolded protein response
资金
- La ligue Contre le Cancer
- INCa
- Canceropole PACA
- INSERM
- Canadian Institutes of Health Research (MOP) [PJT166029]
This study uncovers a new role for NUPR1 in the unfolded protein response and the integrated stress response, involving interaction with eIF2 alpha to promote efficient stress response. Loss of NUPR1 leads to sustained eIF2 alpha phosphorylation and slower poststress protein synthesis recovery in cells.
Nuclear protein 1 (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 debated. In this study, we uncover a new role for NUPR1, participating in the unfolded protein response (UPR) and the integrated stress response. Biochemical results and ultrastructural morphological observations revealed alterations in the UPR of acinar cells of germline-deleted NUPR1 murine models, consistent with the inability to restore general protein synthesis after stress induction. Bioinformatic analysis of NUPR1-interacting partners showed significant enrichment in translation initiation factors, including eukaryotic initiation factor (eIF) 2 alpha. Co-immunoprecipitation and proximity ligation assays confirmed the interaction between NUPR1 and eIF2 alpha and its phosphorylated form (p-eIF2 alpha). Furthermore, our data suggest loss of NUPR1 in cells results in maintained eIF2 alpha phosphorylation and evaluation of nascent proteins by click chemistry revealed that NUPR1-depleted PANC-1 cells displayed a slower poststress protein synthesis recovery when compared to wild-type. Combined, these data propose 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 eIF2 alpha.
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