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PERK-mediated induction of microRNA-483 disrupts cellular ATP homeostasis during the unfolded protein response
- Source :
- The Journal of biological chemistry, vol 295, iss 1
- Publication Year :
- 2020
- Publisher :
- eScholarship, University of California, 2020.
-
Abstract
- Endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR), which reduces levels of misfolded proteins. However, if ER homeostasis is not restored and the UPR remains chronically activated, cells undergo apoptosis. The UPR regulator, PKR-like endoplasmic reticulum kinase (PERK), plays an important role in promoting cell death when persistently activated; however, the underlying mechanisms are poorly understood. Here, we profiled the microRNA (miRNA) transcriptome in human cells exposed to ER stress and identified miRNAs that are selectively induced by PERK signaling. We found that expression of a PERK-induced miRNA, miR-483, promotes apoptosis in human cells. miR-483 induction was mediated by a transcription factor downstream of PERK, activating transcription factor 4 (ATF4), but not by the CHOP transcription factor. We identified the creatine kinase brain-type (CKB) gene, encoding an enzyme that maintains cellular ATP reserves through phosphocreatine production, as being repressed during the UPR and targeted by miR-483. We found that ER stress, selective PERK activation, and CKB knockdown all decrease cellular ATP levels, leading to increased vulnerability to ER stress-induced cell death. Our findings identify miR-483 as a downstream target of the PERK branch of the UPR. We propose that disruption of cellular ATP homeostasis through miR-483-mediated CKB silencing promotes ER stress-induced apoptosis.
- Subjects :
- F1F0-ATPase
translation control
activating transcription factor-4
Biochemistry & Molecular Biology
fluorescence resonance energy transfer
translation
Apoptosis
Medical and Health Sciences
eIF-2 Kinase
Adenosine Triphosphate
Genetics
Humans
Homeostasis
2.1 Biological and endogenous factors
Aetiology
Creatine Kinase
creatine kinase B
microRNA
BB Form
stress response
unfolded protein response
Biological Sciences
Stem Cell Research
Activating Transcription Factor 4
PKR-like endoplasmic reticulum kinase
ATP
MicroRNAs
endoplasmic reticulum
HEK293 Cells
Hela Cells
Chemical Sciences
Unfolded Protein Response
endoplasmic reticulum stress
Generic health relevance
HeLa Cells
Biotechnology
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- The Journal of biological chemistry, vol 295, iss 1
- Accession number :
- edsair.od.......325..db6b8445ddd5d85c684371e634e97175