Neuron-specific translational control shift ensures proteostatic resilience during ER stress.
ANG
HRI
PERK
neuron-specific
translational control
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
16 08 2022
16 08 2022
Historique:
revised:
06
06
2022
received:
21
12
2021
accepted:
09
06
2022
pubmed:
7
7
2022
medline:
18
8
2022
entrez:
6
7
2022
Statut:
ppublish
Résumé
Proteostasis is essential for cellular survival and particularly important for highly specialised post-mitotic cells such as neurons. Transient reduction in protein synthesis by protein kinase R-like endoplasmic reticulum (ER) kinase (PERK)-mediated phosphorylation of eukaryotic translation initiation factor 2α (p-eIF2α) is a major proteostatic survival response during ER stress. Paradoxically, neurons are remarkably tolerant to PERK dysfunction, which suggests the existence of cell type-specific mechanisms that secure proteostatic stress resilience. Here, we demonstrate that PERK-deficient neurons, unlike other cell types, fully retain the capacity to control translation during ER stress. We observe rescaling of the ATF4 response, while the reduction in protein synthesis is fully retained. We identify two molecular pathways that jointly drive translational control in PERK-deficient neurons. Haem-regulated inhibitor (HRI) mediates p-eIF2α and the ATF4 response and is complemented by the tRNA cleaving RNase angiogenin (ANG) to reduce protein synthesis. Overall, our study elucidates an intricate back-up mechanism to ascertain translational control during ER stress in neurons that provides a mechanistic explanation for the thus far unresolved observation of neuronal resilience to proteostatic stress.
Identifiants
pubmed: 35791631
doi: 10.15252/embj.2021110501
pmc: PMC9379547
doi:
Substances chimiques
Eukaryotic Initiation Factor-2
0
Activating Transcription Factor 4
145891-90-3
eIF-2 Kinase
EC 2.7.11.1
Banques de données
GEO
['GSE200742']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e110501Informations de copyright
© 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
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