Neurons shift translational control to secure proteostatic resilience during ER stress
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ABSTRACT:
PROVIDER: PRJNA826463 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18743531_1.fastq.gz | Fastqsanger.gz | |||
| SRR18743531_2.fastq.gz | Fastqsanger.gz | |||
| SRR18743532_1.fastq.gz | Fastqsanger.gz | |||
| SRR18743532_2.fastq.gz | Fastqsanger.gz | |||
| SRR18743533_1.fastq.gz | Fastqsanger.gz |
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Project description:Proteostasis is essential for survival and particularly important for highly specialized post mitotic cells like neurons. Transient reduction of protein synthesis by protein kinase R–like endoplasmic reticulum (ER) kinase (PERK)-mediated phosphorylation of eukaryotic translation initiation factor 2α (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. We employed PERK-deficient neuron and astrocyte monocultures to investigate the mechanisms underlying neuron-specific ER stress resilience in the absence of PERK.
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Project description:Proteostasis is essential for cellular survival, and particularly important for highly specialized post-mitotic cells like neurons. Transient reduction of 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 of protein synthesis is fully retained. We identify two molecular pathways that jointly drive translational control in PERK-deficient neurons. Heme-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.
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