NUPR1 interacts with eIF2α and is required for resolution of the ER stress response in pancreatic tissue.
Acinar Cells
/ metabolism
Animals
Blotting, Western
Cell Line, Tumor
DNA-Binding Proteins
/ genetics
Endoplasmic Reticulum Stress
/ genetics
Eukaryotic Initiation Factor-2
/ genetics
Gene Expression Regulation
Humans
Mice, Knockout
Microscopy, Electron, Transmission
Neoplasm Proteins
/ genetics
Pancreas
/ cytology
Protein Binding
Reverse Transcriptase Polymerase Chain Reaction
Unfolded Protein Response
/ genetics
ER stress
NUPR1
eIF2α
protein translation
unfolded protein response
Journal
The FEBS journal
ISSN: 1742-4658
Titre abrégé: FEBS J
Pays: England
ID NLM: 101229646
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
revised:
20
11
2020
received:
22
05
2020
accepted:
04
01
2021
pubmed:
7
1
2021
medline:
3
8
2021
entrez:
6
1
2021
Statut:
ppublish
Résumé
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) 2α. Co-immunoprecipitation and proximity ligation assays confirmed the interaction between NUPR1 and eIF2α and its phosphorylated form (p-eIF2α). Furthermore, our data suggest loss of NUPR1 in cells results in maintained eIF2α 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 eIF2α.
Substances chimiques
DNA-Binding Proteins
0
Eukaryotic Initiation Factor-2
0
Neoplasm Proteins
0
Nupr1 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4081-4097Subventions
Organisme : CIHR
ID : MOP#PJT166029
Pays : Canada
Informations de copyright
© 2021 Federation of European Biochemical Societies.
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