Abstract
The accumulation of misfolded proteins in the endoplasmic reticulum (ER) lumen due to the disruption of the homeostatic system of the ER leads to the induction of the ER stress response. Cellular stress-induced pathways globally transform genes expression on both the transcriptional and post-transcriptional levels with small RNA involvement as regulators of the stress response. The modulation of small RNA processing might represent an additional layer of a complex stress response program. However, it is poorly understood. Here, we studied changes in expression and small RNAs processing upon ER stress in Jurkat T-cells. Induced by ER-stress, depletion of miRNAs among small RNA composition was accompanied by a global decrease of 3′ mono-adenylated, mono-cytodinylated and a global increase of 3′ mono-uridinylated miRNA isoforms. We observed the specific subset of differentially expressed microRNAs, and also the dramatic induction of 32-nt tRNA fragments precisely phased to 5′ and 3′ ends of tRNA from a subset of tRNA isotypes. The induction of these tRNA fragments was linked to Angiogenin RNase, which mediates translation inhibition. Overall, the global perturbations of the expression and processing of miRNAs and tiRNAs were the most prominent features of small RNA transcriptome changes upon ER stress.
Highlights
With its protein maturation machinery and other energy-intensive processes, the endoplasmic reticulum (ER) is highly sensitive to numerous factors, such as toxins, excessive protein influx, nutrition and energy deprivation, redox imbalance, and the depletion of Сa2+ storage
For more detailed assessment of DTT effects on cells, we performed Affymetrix whole transcriptome gene expression analysis with subsequent functional annotation of the classes of genes that are enriched among the genes differentially regulated in DTT-treated cells using Gene Set Enrichment Analysis (GSEA)[31]
GSEA revealed 35 gene sets upregulated at FDR < 25% (Table S2); 15 gene sets were downregulated at FDR < 25% (Table S3)
Summary
With its protein maturation machinery and other energy-intensive processes, the endoplasmic reticulum (ER) is highly sensitive to numerous factors, such as toxins, excessive protein influx, nutrition and energy deprivation, redox imbalance, and the depletion of Сa2+ storage. UPR of high eukaryotes includes three major signaling pathways mediated by three ER transmembrane sensors: protein kinase RNA (PKR)-like ER kinase (PERK), activating transcription factor-6 (ATF6) and inositol-requiring protein-1 (IRE1)[4] The activation of these sensors results in the production of b-Zip transcription factors, which transduce information to the nucleus and activate the expression of numerous genes involved in protein folding and degradation, amino acid metabolism, redox homeostasis and apoptosis[3]. TTR proteins play an important role in the cellular stress response through the stabilization of several stress-related ARE-containing mRNAs, such as hsp[705] Another important post-transcriptional regulator involved in transcriptome remodeling is microRNA11,12–14, which has a significant impact on different pathological processes. Diverse post-transcriptional modifications of miRNAs, such as nucleotide additions, have distinct functional consequences[17,18]
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