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Two distinct Trypanosoma eIF4F complexes co-exist, bind different mRNAs and are regulated during nutritional stress

ABSTRACT: Many eIF4F subunits and PABP paralogues are found in trypanosomes: six eIF4E, five eIF4G, one eIF4A and two PABPs. They are expressed simultaneously and assemble into different complexes, contrasting the situation in metazoans that use distinct complexes in different cell types or developmental stages. Each eIF4F complex has its own proteins, mRNAs and, consequently, a distinct function. We set out to study the function and regulation of the two major eIF4F complexes of Trypanosoma cruzi. We identified the associated proteins and mRNAs of eIF4E3 and eIF4E4 in cells in exponential growth and in nutritional stress. Upon stress, eIF4G/eIF4A and PABP remain associated to the eIF4E, but the association with other 43S pre-initiation factors decreases, indicating that ribosome attachment is impaired. Most eIF4E3-associated mRNAs encode for metabolic proteins, while eIF4E4 associate to mRNAs encoding ribosomal proteins. Interestingly, for both eIF4E3/4, more mRNAs were associated in stressed cells than in non-stressed cells, even though stress causes ribosome disassembly. In summary, trypanosomes have two co-existing eIF4F complexes involved in translation of distinct mRNA cohorts important for growth. Under stress conditions, both complexes exit translation but remain bound to their mRNA targets.

ORGANISM(S): Trypanosoma cruzi

PROVIDER: GSE263777 | GEO | 2024/04/14

REPOSITORIES: GEO

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Project description:Accumulating data indicate translation plays a role in cancer biology, particularly its rate limiting stage of initiation. Despite this evolving recognition, the function and importance of specific translation initiation factors is unresolved. The eukaryotic translation initiation complex eIF4F consists of eIF4E and eIF4G at a 1:1 ratio. Although it is expected that they display interdependent functions, several publications suggest independent mechanisms. This study is the first to directly assess the relative contribution of eIF4F components to the expressed cellular proteome, transcription factors, microRNAs, and phenotype in a malignancy known for extensive protein synthesis- multiple myeloma (MM). Previously, we have shown that eIF4E/eIF4GI attenuation (siRNA/ Avastin) deleteriously affected MM cells' fate and reduced levels of eIF4E/eIF4GI established targets. Here, we demonstrated that eIF4E/eIF4GI indeed have individual influences on cell proteome. We used an objective, high throughput assay of mRNA microarrays to examine the significance of eIF4E/eIF4GI silencing to several cellular facets such as transcription factors, microRNAs and phenotype. We showed different imprints for eIF4E and eIF4GI in all assayed aspects. These results promote our understanding of the relative contribution and importance of eIF4E and eIF4GI to the malignant phenotype and shed light on their function in eIF4F translation initiation complex. This study concentrated on a particular cancer model and studied the role of eIF4E and eIF4GI in the design of the cells' proteome. We used an unbiased, high throughput system to evaluate the individual importance of eIF4E and eIF4GI levels in MM. We used models of eIF4E or eIF4GI knocked down (KD) MM cell line RPMI 8226 and profiled their respective translated transcription factors (TF), often tumor suppressors or oncogenes. Furthermore, we assessed the KDs' microRNAs repertoires and cells' phenotype. Significant differences were observed between eIF4E and eIF4GI knockdown imprints.

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Two distinct Trypanosoma eIF4F complexes co-exist, bind different mRNAs and are regulated during nutritional stress

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