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1.
Nat Commun ; 15(1): 1382, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38360885

RESUMO

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.


Assuntos
Proteínas de Ligação ao Cálcio , Chaperonas Moleculares , Fator 1 de Elongação de Peptídeos , Dobramento de Proteína , Ribossomos , Biossíntese de Proteínas , Proteostase , Ribossomos/genética , Ribossomos/metabolismo , Humanos , Proteínas de Ligação ao Cálcio/metabolismo , Chaperonas Moleculares/metabolismo , Fator 1 de Elongação de Peptídeos/metabolismo
2.
Elife ; 82019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31552827

RESUMO

Hsf1 is an ancient transcription factor that responds to protein folding stress by inducing the heat-shock response (HSR) that restore perturbed proteostasis. Hsp70 chaperones negatively regulate the activity of Hsf1 via stress-responsive mechanisms that are poorly understood. Here, we have reconstituted budding yeast Hsf1-Hsp70 activation complexes and find that surplus Hsp70 inhibits Hsf1 DNA-binding activity. Hsp70 binds Hsf1 via its canonical substrate binding domain and Hsp70 regulates Hsf1 DNA-binding activity. During heat shock, Hsp70 is out-titrated by misfolded proteins derived from ongoing translation in the cytosol. Pushing the boundaries of the regulatory system unveils a genetic hyperstress program that is triggered by proteostasis collapse and involves an enlarged Hsf1 regulon. The findings demonstrate how an apparently simple chaperone-titration mechanism produces diversified transcriptional output in response to distinct stress loads.


Assuntos
Proteínas de Ligação a DNA/biossíntese , Regulação Fúngica da Expressão Gênica , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico/biossíntese , Proteínas de Saccharomyces cerevisiae/biossíntese , Saccharomyces cerevisiae/metabolismo , Fatores de Transcrição/biossíntese , DNA Fúngico/metabolismo , Temperatura Alta , Ligação Proteica , Dobramento de Proteína , Saccharomyces cerevisiae/efeitos da radiação
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