PMID- 35791631
OWN - NLM
STAT- MEDLINE
DCOM- 20220817
LR  - 20220907
IS  - 1460-2075 (Electronic)
IS  - 0261-4189 (Print)
IS  - 0261-4189 (Linking)
VI  - 41
IP  - 16
DP  - 2022 Aug 16
TI  - Neuron-specific translational control shift ensures proteostatic resilience 
      during ER stress.
PG  - e110501
LID - 10.15252/embj.2021110501 [doi]
LID - e110501
AB  - 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 2alpha 
      (p-eIF2alpha) 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-eIF2alpha 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.
CI  - (c) 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
FAU - Wolzak, Kimberly
AU  - Wolzak K
AUID- ORCID: 0000-0001-9741-6958
AD  - Department of Functional Genomics, Faculty of Science, Center for Neurogenomics 
      and Cognitive Research (CNCR), Vrije Universiteit (VU) Amsterdam, Amsterdam, The 
      Netherlands.
AD  - Functional Genomics Section, Department of Human Genetics, Amsterdam University 
      Medical Centers (UMC) Location Vrije Universiteit, Amsterdam, The Netherlands.
FAU - Nolle, Anna
AU  - Nolle A
AD  - Department of Pathology, Amsterdam University Medical Centers (UMC) Location 
      Vrije Universiteit, Amsterdam, The Netherlands.
FAU - Farina, Margherita
AU  - Farina M
AD  - Department of Functional Genomics, Faculty of Science, Center for Neurogenomics 
      and Cognitive Research (CNCR), Vrije Universiteit (VU) Amsterdam, Amsterdam, The 
      Netherlands.
FAU - Abbink, Truus Em
AU  - Abbink TE
AD  - Department of Child Neurology, Amsterdam University Medical Centers (UMC) 
      Location Vrije Universiteit, Amsterdam, The Netherlands.
FAU - van der Knaap, Marjo S
AU  - van der Knaap MS
AD  - Department of Functional Genomics, Faculty of Science, Center for Neurogenomics 
      and Cognitive Research (CNCR), Vrije Universiteit (VU) Amsterdam, Amsterdam, The 
      Netherlands.
AD  - Department of Child Neurology, Amsterdam University Medical Centers (UMC) 
      Location Vrije Universiteit, Amsterdam, The Netherlands.
FAU - Verhage, Matthijs
AU  - Verhage M
AUID- ORCID: 0000-0002-6085-7503
AD  - Department of Functional Genomics, Faculty of Science, Center for Neurogenomics 
      and Cognitive Research (CNCR), Vrije Universiteit (VU) Amsterdam, Amsterdam, The 
      Netherlands.
AD  - Functional Genomics Section, Department of Human Genetics, Amsterdam University 
      Medical Centers (UMC) Location Vrije Universiteit, Amsterdam, The Netherlands.
FAU - Scheper, Wiep
AU  - Scheper W
AUID- ORCID: 0000-0002-1431-4559
AD  - Department of Functional Genomics, Faculty of Science, Center for Neurogenomics 
      and Cognitive Research (CNCR), Vrije Universiteit (VU) Amsterdam, Amsterdam, The 
      Netherlands.
AD  - Functional Genomics Section, Department of Human Genetics, Amsterdam University 
      Medical Centers (UMC) Location Vrije Universiteit, Amsterdam, The Netherlands.
LA  - eng
SI  - GEO/GSE200742
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220706
PL  - England
TA  - EMBO J
JT  - The EMBO journal
JID - 8208664
RN  - 0 (Eukaryotic Initiation Factor-2)
RN  - 145891-90-3 (Activating Transcription Factor 4)
RN  - EC 2.7.11.1 (eIF-2 Kinase)
SB  - IM
MH  - Activating Transcription Factor 4/genetics/metabolism
MH  - Endoplasmic Reticulum/metabolism
MH  - Endoplasmic Reticulum Stress/genetics
MH  - *Eukaryotic Initiation Factor-2/genetics/metabolism
MH  - Neurons/metabolism
MH  - Phosphorylation
MH  - *eIF-2 Kinase/genetics/metabolism
PMC - PMC9379547
OTO - NOTNLM
OT  - ANG
OT  - HRI
OT  - PERK
OT  - neuron-specific
OT  - translational control
EDAT- 2022/07/07 06:00
MHDA- 2022/08/18 06:00
PMCR- 2022/07/06
CRDT- 2022/07/06 03:13
PHST- 2022/06/06 00:00 [revised]
PHST- 2021/12/21 00:00 [received]
PHST- 2022/06/09 00:00 [accepted]
PHST- 2022/07/07 06:00 [pubmed]
PHST- 2022/08/18 06:00 [medline]
PHST- 2022/07/06 03:13 [entrez]
PHST- 2022/07/06 00:00 [pmc-release]
AID - EMBJ2021110501 [pii]
AID - 10.15252/embj.2021110501 [doi]
PST - ppublish
SO  - EMBO J. 2022 Aug 16;41(16):e110501. doi: 10.15252/embj.2021110501. Epub 2022 Jul 
      6.