Depletion of eukaryotic initiation factor 5B (eIF5B) reprograms the cellular transcriptome and leads to activation of en
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ORIGINAL PAPER
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) Kamiko R. Bressler 1,2 & Joseph A. Ross 1,3 & Slava Ilnytskyy 4 & Keiran Vanden Dungen 1 & Katrina Taylor 1 & Kush Patel 1 & Athanasios Zovoilis 1,5,6 & Igor Kovalchuk 4,6 & Nehal Thakor 1,4,5,6,7 Received: 23 June 2020 / Revised: 13 October 2020 / Accepted: 18 October 2020 # Cell Stress Society International 2020
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 Nterminal 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. Keywords Eukaryotic initiation factor 5B (eIF5B) . ER stress . Transcriptome . ISR . ATF4 . JNK
Kamiko R. Bressler, Joseph A. Ross and Slava Ilnytskyy contributed equally to this work. Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s12192-02001174-1. * Nehal Thakor [email protected] 1
Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive W, Lethbridge, Alberta T1K 3M4, Canada
2
Present address: Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, Alberta T2N 4Z6, Canada
3
Present address: Chinook Contract Research Inc., 97 East Lake Ramp NE, Airdrie, Alberta T4A 2 K4, Canada
4
Department of Biological Sciences, University of Lethbridge, 4401 University Drive W, Lethbridge, Alberta T1K 3M4, Canada
5
Canadian Centre for Behavioral Neuroscience (CCBN), Department of Neuroscience,
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