Ribosome movement is not always smooth and is rather often impeded. For ribosome pauses, fundamental issues remain to be addressed, including where ribosomes pause on mRNAs, what kind of RNA/amino acid sequence causes this pause, and the physiological significance of this attenuation of protein synthesis. Here, we survey the positions of ribosome collisions caused by ribosome pauses in humans and zebrafish using modified ribosome profiling. Collided ribosomes, i.e., disomes, emerge at various sites: Pro-Pro/Gly/Asp motifs; Arg-X-Lys motifs; stop codons; and 3' untranslated regions. The electrostatic interaction between the charged nascent chain and the ribosome exit tunnel determines the eIF5A-mediated disome rescue at the Pro-Pro sites. In particular, XBP1u, a precursor of endoplasmic reticulum (ER)-stress-responsive transcription factor, shows striking queues of collided ribosomes and thus acts as a degradation substrate by ribosome-associated quality control. Our results provide insight into the causes and consequences of ribosome pause by dissecting collided ribosomes.
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http://dx.doi.org/10.1016/j.celrep.2020.107610 | DOI Listing |
Trends Cell Biol
December 2024
Center for Gene Expression, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark. Electronic address:
Next to their essential role as protein production factories, ribosomes serve as molecular sensors of cell stress. Stalled and collided ribosomes trigger specific stress signaling, including the ribotoxic stress response (RSR). The RSR is initiated by the mitogen-activated protein (MAP)-3 kinase ZAKα in response to a plethora of translational aberrations, leading to activation of the stress-activated MAP kinases p38 and jun N-terminal kinase (JNK).
View Article and Find Full Text PDFPLoS Biol
December 2024
Department of Frontier Life Sciences, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto, Japan.
Quality control of translation is crucial for maintaining cellular and organismal homeostasis. Obstacles in translation elongation induce ribosome collision, which is monitored by multiple sensor mechanisms in eukaryotes. The E3 ubiquitin ligase Znf598 recognizes collided ribosomes, triggering ribosome-associated quality control (RQC) to rescue stalled ribosomes and no-go decay (NGD) to degrade stall-prone mRNAs.
View Article and Find Full Text PDFNature
January 2025
Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
Mol Cell
December 2024
Department of Biology, Washington University in St. Louis, St. Louis, MO 63130, USA. Electronic address:
In yeast, multiprotein bridging factor 1 (Mbf1) has been proposed to function in the integrated stress response (ISR) as a transcriptional coactivator by mediating a direct interaction between general transcription machinery and the process's key effector, Gcn4. However, mounting evidence has demonstrated that Mbf1 (and its human homolog EDF1) is recruited to collided ribosomes, a known activator of the ISR. In this study, we connect these otherwise seemingly disparate functions of Mbf1.
View Article and Find Full Text PDFNature
November 2024
Department of Structural Cell Biology, Max Planck Institute of Biochemistry, Martinsried, Germany.
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