1. Multiprotein bridging factor 1 is required for robust activation of the integrated stress response on collided ribosomes.
- Author
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Kim, Kyusik Q., Li, Jeffrey J., Nanjaraj Urs, Ankanahalli N., Pacheco, Miguel E., Lasehinde, Victor, Denk, Timo, Tesina, Petr, Tomomatsu, Shota, Matsuo, Yoshitaka, McDonald, Elesa, Beckmann, Roland, Inada, Toshifumi, Green, Rachel, and Zaher, Hani S.
- Abstract
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. Our biochemical and structural analyses reveal that Mbf1 functions as a core ISR factor by interacting with collided ribosomes to mediate Gcn2 activation. We further show that Mbf1 serves no role as a transcriptional coactivator of Gcn4. Instead, Mbf1 is required for optimal stress-induced eukaryotic initiation factor 2α (eIF2α) phosphorylation and downstream de-repression of GCN4 translation. Collectively, our data establish that Mbf1 functions in ISR signaling by acting as a direct sensor of stress-induced ribosome collisions. [Display omitted] • Optimal Gcn2-mediated eIF2α phosphorylation requires the presence of Mbf1 • Mbf1 exhibits no transcriptional coactivation function with Gcn4 • Mbf1 recruitment to collided ribosomes is required for robust Gcn2 activation • Similar to Gcn20, Mbf1 is a bona fide activator of Gcn2 during induction of the ISR Mbf1 was proposed to function as a transcriptional coactivator during induction of the ISR, bridging a physical connection between Gcn4 and the transcription machinery. Kim et al. challenge this, demonstrating that yeast Mbf1 functions in the ISR through its recruitment to collided ribosomes on which it contributes to Gcn2 activation. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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