Fusel Alcohols Regulate Translation Initiation by Inhibiting eIF2B to Reduce Ternary Complex in a Mechanism That May Involve Altering the Integrity and Dynamics of the eIF2B Body
| Autor: | Mark P. Ashe, Graham D. Pavitt, Paul F. G. Sims, Susan G. Campbell, Christian D. Griffiths, Peter J. Reid, Eleanor Taylor, Daniela Delneri, Richard J. Harrison, John W. Slaven |
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| Rok vydání: | 2010 |
| Předmět: |
Cell Physiology
Saccharomyces cerevisiae Proteins Recombinant Fusion Proteins Molecular Sequence Data Saccharomyces cerevisiae Biology Guanosine Diphosphate 03 medical and health sciences 0302 clinical medicine Eukaryotic translation Humans Life Science Protein Phosphatase 2 Molecular Biology Ternary complex 030304 developmental biology Fusel alcohol 0303 health sciences eIF2 Base Sequence Translation (biology) Articles Cell Biology Eukaryotic Initiation Factor-2B Protein Subunits Biochemistry Alcohols Multiprotein Complexes Protein Biosynthesis Mutation Transfer RNA eIF2B biology.protein Guanosine Triphosphate Guanine nucleotide exchange factor 030217 neurology & neurosurgery |
| Zdroj: | Molecular Biology of the Cell 21 (2010) 13 Molecular Biology of the Cell, 21(13), 2202-2216 Molecular Biology of the Cell |
| ISSN: | 1939-4586 1059-1524 |
| DOI: | 10.1091/mbc.e09-11-0962 |
| Popis: | This study highlights a connection between the eIF2B body and the regulation of translation initiation as a response to stress in Saccharomyces cerevisiae. Fusel alcohols are involved in signaling nitrogen scarcity to the cell and they inhibit protein synthesis by preventing the movement of the eIF2B body throughout the cell. Recycling of eIF2-GDP to the GTP-bound form constitutes a core essential, regulated step in eukaryotic translation. This reaction is mediated by eIF2B, a heteropentameric factor with important links to human disease. eIF2 in the GTP-bound form binds to methionyl initiator tRNA to form a ternary complex, and the levels of this ternary complex can be a critical determinant of the rate of protein synthesis. Here we show that eIF2B serves as the target for translation inhibition by various fusel alcohols in yeast. Fusel alcohols are endpoint metabolites from amino acid catabolism, which signal nitrogen scarcity. We show that the inhibition of eIF2B leads to reduced ternary complex levels and that different eIF2B subunit mutants alter fusel alcohol sensitivity. A DNA tiling array strategy was developed that overcame difficulties in the identification of these mutants where the phenotypic distinctions were too subtle for classical complementation cloning. Fusel alcohols also lead to eIF2α dephosphorylation in a Sit4p-dependent manner. In yeast, eIF2B occupies a large cytoplasmic body where guanine nucleotide exchange on eIF2 can occur and be regulated. Fusel alcohols impact on both the movement and dynamics of this 2B body. Overall, these results confirm that the guanine nucleotide exchange factor, eIF2B, is targeted by fusel alcohols. Moreover, they highlight a potential connection between the movement or integrity of the 2B body and eIF2B regulation. |
| Databáze: | OpenAIRE |
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