Chp1 is a dedicated chaperone at the ribosome that safeguards eEF1A biogenesis

Melania Minoia, Jany Quintana-Cordero, Katharina Jetzinger, Ilgin Eser Kotan, Kathryn Jane Turnbull, Michela Ciccarelli, Anna E. Masser, Dorina Liebers, Eloïse Gouarin, Marius Czech, Vasili Hauryliuk, Bernd Bukau, Günter Kramer and Claes Andréasson ()
Additional contact information
Melania Minoia: Stockholm University
Jany Quintana-Cordero: Stockholm University
Katharina Jetzinger: Stockholm University
Ilgin Eser Kotan: Center for Molecular Biology of the University of Heidelberg (ZMBH), DKFZ-ZMBH Alliance
Kathryn Jane Turnbull: Rigshospitalet
Michela Ciccarelli: Stockholm University
Anna E. Masser: Stockholm University
Dorina Liebers: Center for Molecular Biology of the University of Heidelberg (ZMBH), DKFZ-ZMBH Alliance
Eloïse Gouarin: Stockholm University
Marius Czech: Stockholm University
Vasili Hauryliuk: Lund University
Bernd Bukau: Center for Molecular Biology of the University of Heidelberg (ZMBH), DKFZ-ZMBH Alliance
Günter Kramer: Center for Molecular Biology of the University of Heidelberg (ZMBH), DKFZ-ZMBH Alliance
Claes Andréasson: Stockholm University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-45645-w

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