Depletion of eukaryotic initiation factor 5B (eIF5B) reprograms the cellular transcriptome and leads to activation of endoplasmic reticulum (ER) stress and c-Jun N-terminal Kinase (JNK).
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Date
2021
Authors
Bressler, Kamiko R.
Ross, Joseph A.
Ilnytskyy, Slava
Vanden Dungen, Keiran
Taylor, Katrina
Patel, Kush
Zovoilis, Athanasios
Kovalchuk, Igor
Thakor, Nehal
Journal Title
Journal ISSN
Volume Title
Publisher
Springer
Abstract
During the integrated stress response (ISR), global translation initiation is attenuated; however, noncanonical mechanisms allow for the continued translation of specific transcripts. Eukaryotic initiation factor 5B (eIF5B) has been shown to play a critical role in canonical translation as well as in noncanonical mechanisms involving internal ribosome entry site (IRES) and upstream open reading frame (uORF) elements. The uORF-mediated translation regulation of activating transcription factor 4 (ATF4) mRNA plays a pivotal role in the cellular ISR. Our recent study confirmed that eIF5B depletion removes uORF2-mediated repression of ATF4 translation, which results in the upregulation of growth arrest and DNA damage-inducible protein 34 (GADD34) transcription. Accordingly, we hypothesized that eIF5B depletion may reprogram the transcriptome profile of the cell. Here, we employed genome-wide transcriptional analysis on eIF5B-depleted cells. Further, we validate the up- and downregulation of several transcripts from our RNA-seq data using RT-qPCR. We identified upregulated pathways including cellular response to endoplasmic reticulum (ER) stress, and mucin-type O-glycan biosynthesis, as well as downregulated pathways of transcriptional misregulation in cancer and T cell receptor signaling. We also confirm that depletion of eIF5B leads to activation of the c-Jun N-terminal kinase (JNK) arm of the mitogen-activated protein kinase (MAPK) pathway. This data suggests that depletion of eIF5B reprograms the cellular transcriptome and influences critical cellular processes such as ER stress and ISR.
Description
Accepted author manuscript.
Keywords
Eukaryotic initiation factor 5B (eIF5B) , ER stress , Transcriptome , ISR , ATF4 , JNK
Citation
Bressler, K. R., Ross, J. A., Ilnytskyy, S., Vanden Dungen, K., Taylor, K., Patel, K., Zovoilis, A., Kovalchuk, I., & Thakor, N (2021). Depletion of eukaryotic initiation factor 5B (eIF5B) reprograms the cellular transcriptome and leads to activation of endoplasmic reticulum (ER) stress and c-Jun N-terminal Kinase (JNK). Cell Stress and Chaperones, 26, 253-264. https://doi.org/10.1007/s12192-020-01174-1