Investigating the targets and mechanism of specialized translation regulation
| Autor: | Fleming, Rebecca Hamilton |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: | |
| DOI: | 10.48617/etd.27 |
| Popis: | In response to cell stress, our cells inhibit global protein synthesis. This global protein shutoff is well characterized. In contrast, how cells reprogram the translation machinery for selective gene expression during global protein shutoff remains poorly understood. Our work demonstrates that two multi-subunit complexes are important for selective gene expression during cell stress. First being the noncanonical 5���cap-binding protein eIF3d is activated in response to metabolic stress. The activation of eIF3d requires reduced CK2-mediated phosphorylation near the eIF3d cap-binding pocket. Unphosphorylated eIF3d controls a gene program containing factors important for glucose homeostasis. The eIF3d-directed translation pathway is essential for cell adaptation and survival which regulates the cellular response to metabolic stress. Secondly, evidence suggests the ribosome may also play a role in selective gene expression during inhibition of global protein synthesis. Heterogeneity of ribosome composition has been shown to be one way the ribosome gains specificity for select groups of mRNA transcripts. In particular, rpL40 is necessary for translation initiation of the VSV mRNA and is sub-stoichiometric in free subunits. Our work demonstrates that the cell regulates rpL40 occupancy in the ribosome during stress and selectively translates cellular mRNA targets. A majority of these targets respond to stress and are important for cell homeostasis. To help determine the mechanism of rpL40-mediated translation, we developed a nanobody to separately isolate ribosomes with or without rpL40. Together this work shows that selective gene translation is regulated by multi-subunit complexes that have various functions within canonical and noncanonical translation regulation. |
| Databáze: | OpenAIRE |
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