TRANSLATION CONTROL AND CO-TRANSLATIONAL PROCESS IN HEALTH AND DISEASE
| Autoři | |
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| Rok publikování | 2025 |
| Druh | Konferenční abstrakty |
| Fakulta / Pracoviště MU | |
| Citace | |
| Přiložené soubory | |
| Popis | Co-translational quality control is triggered as a response to translational stalling events. Yet, different molecular mechanisms are employed for the recognition of these stalls and to trigger downstream rescue and quality control pathways. While the recognition of individual stalled ribosomes is poorly understood, the use of collided ribosomes as a proxy for the recognition of translation problems in the cell is conserved from bacteria to humans1–3. In eukaryotes, co -translational quality-control processes triggered by ribosome collisions accomplish several tasks and eventually trigger stress response signalling pathways4. As a key pathway affecting host translation the integrated stress response (ISR) is a highly conserved eukaryotic mechanism for integrating multiple signals to reprogram gene expression. These signals are conveyed by protein kinases that phosphorylate the ? subunit of the initiation factor 2 (eIF2). Mammals have four known eIF2? kinases: GCN2, PERK, HRI, and PKR, which are activated in response to amino-acid starvation, ER stress, cytoplasmic protein misfolding and viral infection, respectively5. We examined the function of Mbf1 during induction of the ISR, and the role of ribosome binding in modulating this activity. We present a cryo-EM structure, in which Mbf1 acts as a bona fide ribosome collision sensor with its N terminus resolved and bound to the stalled ribosome. Moreover, we show that this region is important for Gcn2 activation, establishing Mbf1 as an integral component of the ISR. To ensure the translation of their own mRNAs, viruses take control of the host protein synthesis machinery. Conversely, the host's innate immune defenses often target translation to disable the infected cell's protein synthesis apparatus. At the same time, innate defenses rely on protein production for their activation. As a result, the complex connections among the translation machinery, viruses, and innate immunity remain poorly understood. This applies especially in the field of translation control. Recent work has revealed that ribosome collisions trigger a series of quality control events and activate both a dedicated ribosomeassociated protein quality control (RQC) and the Integrated Stress Response (ISR)4. Here, the mechanisms by which viruses avoid translational shutdown initiated by ribosomal collisions have only begun to emerge. To provide mechanistic understanding of these processes, we employ cryogenic electron microscopy (cryo- EM). To be able to study translation of defined viral mRNAs and allow for straightforward structural characterization, we are developing a cell free in vitro translation system from specifically modified human cells. |
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