Dedicated chaperone at the ribosome safeguards the proteostasis network during eEF1A biogenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA915314 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22878229.fastq.gz | Fastqsanger.gz | |||
| SRR22878230.fastq.gz | Fastqsanger.gz | |||
| SRR22878231.fastq.gz | Fastqsanger.gz | |||
| SRR22878232.fastq.gz | Fastqsanger.gz | |||
| SRR22878233.fastq.gz | Fastqsanger.gz |
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Project description:Cotranslational protein folding depends on general chaperones that engage highly diverse nascent chains at the ribosomes. Here we find that the universal cotranslational machinery adapts to accommodate the challenging biogenesis of abundantly expressed eukaryotic translation elongation factor 1A (eEF1A). During eEF1A synthesis, chaperone Chp1 is recruited to the ribosome with the help of the nascent polypeptide-associated complex (NAC), where it safeguards eEF1A biogenesis. Aberrant eEF1A production triggers instant proteolysis, widespread protein aggregation, activation of Hsf1 stress transcription and compromises cellular fitness. The expression of pathogenic eEF1A2 variants linked to epileptic-dyskinetic encephalopathy is protected by Chp1. Thus, eEF1A is a difficult to fold protein that necessitates dedicated folding factor Chp1 at the ribosomal tunnel exit to protect the eukaryotic cell from proteostasis collapse.
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Project description:Cotranslational protein folding depends on general chaperones that engage highly diverse nascent chains at the ribosomes. It is not clear how this promiscuous mechanism ensure efficient production of challenging clients such as highly expressed proteins. Here we find that the biogenesis of the abundantly expressed eukaryotic translation elongation factor 1A (eEF1A) depends on the dedicated ribosome-associated chaperone Chp1.
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Project description:Cotranslational protein folding depends on general chaperones that engage highly diverse nascent chains at the ribosomes. Here we discover a dedicated ribosome-associated chaperone, Chp1, that rewires the cotranslational folding machinery to assist in the challenging biogenesis of abundantly expressed eukaryotic translation elongation factor 1A (eEF1A). Our results indicate that during eEF1A synthesis, Chp1 is recruited to the ribosome with the help of the nascent polypeptide-associated complex (NAC), where it safeguards eEF1A biogenesis. Aberrant eEF1A production in the absence of Chp1 triggers instant proteolysis, widespread protein aggregation, activation of Hsf1 stress transcription and compromises cellular fitness. The expression of pathogenic eEF1A2 variants linked to epileptic-dyskinetic encephalopathy is protected by Chp1. Thus, eEF1A is a difficult-to-fold protein that necessitates a biogenesis pathway starting with dedicated folding factor Chp1 at the ribosome to protect the eukaryotic cell from proteostasis collapse.
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Project description:PDCD2 is an evolutionarily conserved protein that is essential for cell proliferation and embryonic development. To date, however, the function of PDCD2 underlying its fundamental cellular role has remained elusive. Here we used quantitative proteomics approaches to define the protein-protein interaction network of human PDCD2. Our data revealed that PDCD2 specifically interacts with the 40S ribosomal protein uS5 (RPS2) and that the PDCD2-uS5 complex is assembled co-translationally. Loss of PDCD2 expression leas to defects in the synthesis of small ribosomal subunit that phenocopies a uS5 deficiency. Notably, we showed that PDCD2 is important for the accumulation of soluble uS5 proteins as well as its incorporation into 40S ribosomal subunit. Our findings support that the essential molecular function of PDCD2 is to act as a dedicated chaperone that recognizes the ribosomal protein uS5 co-translationally in the cytoplasm and accompanies uS5 to ribosome assembly sites in the nucleolus. As most dedicated ribosomal protein chaperones have been identified in yeast, our study indicates that similar mechanisms exist in human cells to assist ribosomal proteins coordinate their folding, nuclear import, and assembly in pre-ribosomal particles.
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Project description:PDCD2 functions as an evolutionarily conserved chaperone dedicated for the 40S ribosomal protein uS5
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Project description:Imbalances in endoplasmic reticulum (ER) proteostasis are associated with etiologically-diverse degenerative diseases linked to excessive extracellular protein misfolding and aggregation. Reprogramming of the ER proteostasis environment through genetic activation of the Unfolded Protein Response (UPR)-associated transcription factor ATF6 attenuates secretion and extracellular aggregation of amyloidogenic proteins. Here, we employed a screening approach that included complementary arm-specific UPR reporters and medium-throughput transcriptional profiling to identify non-toxic small molecules that phenocopy the ATF6-mediated reprogramming of the ER proteostasis environment. Comprehensive transcriptome analysis was employed to validate the capacity of three prioritized compounds to remodel the ER proteostasis environment, and to assess the prefential activation of ATF6 transcriptional targets relative to targets of the IRE1/XBP1s and PERK arms of the UPR. HEK293T-Rex and HEK293-DAX cells were treated for 6 hr with vehicle (DMSO), 1 µM Tg, 10 mM TMP (in HEK293DAX), or 10 µM 132, 147 or 263 in biological triplicate at 37 ÌC
2016-07-21 | E-GEOD-84636 | biostudies-arrayexpress
Project description:The unfolded protein response (UPR) maintains endoplasmic reticulum (ER) proteostasis through the activation of transcription factors such as XBP1s and ATF6. The functional consequences of these transcription factors for ER proteostasis remain poorly defined. Here, we describe methodology that enables orthogonal, small molecule-mediated activation of the UPR-associated transcription factors XBP1s and/or ATF6 in the same cell independent of stress. We employ transcriptomics and quantitative proteomics to evaluate ER proteostasis network remodeling owing to the XBP1s and/or ATF6 transcriptional programs. Furthermore, we demonstrate that the three ER proteostasis environments accessible by activating XBP1s and/or ATF6 differentially influence the folding, trafficking, and degradation of destabilized ER client proteins without globally affecting the endogenous proteome. Our data reveal how the ER proteostasis network is remodeled by the XBP1s and/or ATF6 transcriptional programs at the molecular level and demonstrate the potential for selectively restoring aberrant ER proteostasis of pathologic, destabilized proteins through arm-selective UPR-activation. The unfolded protein response adapts endoplasmic reticulum (ER) proteostasis via stress-responsive transcription factors including XBP1s and ATF6. Here, R. Luke Wiseman and colleagues implement technology for the orthogonal, ligand-dependent activation of XBP1s and/or ATF6 in a single cell. They characterize how XBP1s and/or ATF6 activation impacts ER proteostasis pathway composition and function. Adapted ER environments influence the proteostasis of destabilized protein variants without affecting the endogenous proteome. The work informs the development of proteostasis environment-adapting therapeutics for protein misfolding-related diseases. In order to activate both XBP1s and ATF6 in the same cell, we incorporated DHFR.ATF6 and tet-inducible XBP1s into a HEK293T-REx cell line stably expressing the tet-repressor. The HEK293DYG control cell line expresses tet-inducible eGFP and DHFR.YFP and is used as a control to demonstrate that the addition of doxycycline (dox) and trimethoprim (TMP) do not induce UPR genes. HEK293DYG cells were treated for 12 h with vehicle or 1 μg/mL dox and 10 μM TMP in biological triplicate. Cells were harvested and RNA was extracted using the RNeasy Mini Kit (Qiagen). Genomic DNA was removed by on-column digestion using the RNase-free DNase Set (Qiagen). Data from HEK293DYG cells showed no significant overlap in the ligand-treated transcriptomes obtained from HEK293DAX cells.
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