Multiprotein bridging factor 1 is required for robust activation of the integrated stress response on collided ribosomes
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.
Authors
- Roland Beckmann (ORCID: https://orcid.org/0000-0003-4291-3898)
- Timo Denk (ORCID: https://orcid.org/0000-0002-0761-3294)
- Kyusik Q. Kim (ORCID: https://orcid.org/0000-0002-1832-2070)
- Petr Těšina (ORCID: https://orcid.org/0000-0002-5227-1799)
- Ankanahalli N. Nanjaraj Urs (ORCID: https://orcid.org/0000-0002-1357-6733)
- Rachel Green (ORCID: https://orcid.org/0000-0001-9337-2003)
- Jeffrey J. Li
- Shota Tomomatsu
- Toshifumi Inada (ORCID: https://orcid.org/0000-0002-2695-588X)
- E. Robert McDonald (ORCID: https://orcid.org/0000-0002-7209-4216)
- Miguel Pacheco (ORCID: https://orcid.org/0000-0002-9605-7954)
- Hani Zaher (ORCID: https://orcid.org/0000-0002-7424-3617)
- Yoshitaka Matsuo (ORCID: https://orcid.org/0000-0001-9895-0028)
- Victor Lasehinde (ORCID: https://orcid.org/0000-0001-6317-9253)
Institutions
- Howard Hughes Medical Institute (US)
- Johns Hopkins University (US)
- Washington University in St. Louis (US)
- The University of Tokyo (JP)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Molecular Cell
- Published
- 2024-11-19
- DOI
- https://doi.org/10.1016/j.molcel.2024.10.029
- Citations
- 10
- Primary Topic
- Signaling Pathways in Disease
- Type
- article
- Field-Weighted Citation Impact
- 2.34
Funders
- Howard Hughes Medical Institute
- European Commission
- Deutsche Forschungsgemeinschaft
- Ministry of Education, Culture, Sports, Science and Technology
- National Institutes of Health
- Japan Society for the Promotion of Science