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Nascent chain folding status modulates ribosome dynamics and mRNA stability through the ribosome-associated chaperone Zuo1

ABSTRACT: Ribosome dynamics during mRNA translation elongation regulate mRNA stability. Yet, known regulators of ribosome transit, such as codon usage, cannot fully explain transcriptome-wide decay rates. Here, we demonstrate that nascent polypeptide folding status modulates elongation rates, with Zuotin (Zuo1) serving as an essential mediator, and this also influences mRNA stability. Using reporter constructs encoding co-translationally unstructured proteins and RNA sequencing under proteotoxic stress, we show that Zuo1 is required for the selective destabilization of transcripts whose nascent peptides fail to fold properly. This process is independent of codon optimality but relies on the co-translational mRNA decay factor Not5, which detects slowed ribosomes. 35S labeling indicates that nascent peptide folding defects correlate with reduced elongation rates in a Zuo1-dependent manner, and ribosome profiling reveals that global protein misfolding induces Zuo1-dependent ribosome pausing. These findings position Zuo1 as a key mediator linking nascent peptide folding status to ribosome dynamics and mRNA stability. Furthermore, this work suggests an expanded role for Not5 beyond codon optimality sensing.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE319659 | GEO | 2026/07/24

REPOSITORIES: GEO

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Nascent chain misfolding slows translation and stimulates co-translational mRNA decay

Project description:Ribosome dynamics during mRNA translation elongation regulate mRNA stability. Yet, codon usage, a known regulator of ribosome transit, cannot fully explain transcriptome-wide decay rates. Here, we demonstrate that nascent polypeptide folding modulates elongation rates, with Zuotin (Zuo1) serving as an essential mediator. Using reporter constructs and RNA sequencing, we show that Zuo1 is essential for the selective destabilization of transcripts encoding co-translationally misfolded proteins. This process is independent of codon optimality but relies on co-translational mRNA decay factor Not5, which detects slowed ribosomes. Ribosome profiling reveals that global protein misfolding induces Zuo1-dependent ribosome stalling. 35S labeling confirms that nascent peptide misfolding directly slows elongating ribosomes in a Zuo1-dependent manner. These findings highlight Zuo1 as a pivotal mediator linking nascent peptide folding to ribosome dynamics and thereby mRNA stability, unveiling a novel mechanism of mRNA regulation driven by protein products. Furthermore, this work expands Not5’s role beyond codon optimality sensing.

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Nascent chain folding status modulates ribosome dynamics and mRNA stability through the ribosome-associated chaperone Zuo1

Project description:Ribosome dynamics during mRNA translation elongation regulate mRNA stability. Yet, known regulators of ribosome transit, such as codon usage, cannot fully explain transcriptome-wide decay rates. Here, we demonstrate that nascent polypeptide folding modulates elongation rates, with Zuotin (Zuo1) serving as an essential mediator. Using reporter constructs encoding co-translationally unstructured proteins and RNA sequencing under proteotoxic stress, we show that Zuo1 is required for selective destabilization of transcripts whose nascent peptides fail to fold properly. This process relies on the co-translational mRNA decay factor Not5, which detects slowed ribosomes. 35S labeling indicates that nascent peptide folding defects correlate with reduced elongation rates in a Zuo1-dependent manner, and ribosome profiling reveals that global protein misfolding induces Zuo1-dependent ribosome pausing. These findings position Zuo1 as a key mediator linking nascent peptide folding status to ribosome dynamics and mRNA stability. Furthermore, this work suggests an expanded role for Not5 beyond codon optimality sensing.

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Translation switch from initiation to elongation needs Not4 and Not5 collaboration

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