Differential processing of small RNAs during endoplasmic reticulum stress

Mesitov, Mikhail V.; Soldatov, Ruslan A.; Zaichenko, Danila M.; Malakho, Sophie G.; Klementyeva, Tatyana S.; Sokolovskaya, Alice; Kubatiev, A. A.; Mironov, Andrey A.; Московцев, А. А.

doi:10.1038/srep46080

Cited by 22 publications

(14 citation statements)

References 90 publications

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“…Although our studies were similar to a previous report on Jurkat pre-T- cells that did not examine piRNAs 46 , we found a decrease in the relative quantity of miRNA-mapped reads and also noted a large relative increase in piRNA-mapped reads (3–4 fold) that were most significantly induced during the cell fate decision stage (6 hours). Furthermore, different mechanisms of ER stress induction had very similar effects on piRNA expression profiles, and resulted mainly in induction of these RNAs, whereas the total miRNAs were reduced.…”

Section: Discussionsupporting

confidence: 89%

“…Despite these important discoveries, the majority of research has been performed in cancer cell lines. Recently, a class of small non-coding RNAs, miRNA, has been linked to the unfolded protein response pathway, and shown that these miRNAs through their posttranscriptional effects on multiple components of UPR can determine cell fate during ER stress 45 , 46 (reviewed in 7 , 47 , 48 ). Although this miRNA’s role in UPR remains extensively studied, the functions of other small non-coding RNA classes in this pathway remain relatively unknown 46 .…”

Section: Discussionmentioning

confidence: 99%

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PIWI proteins contribute to apoptosis during the UPR in human airway epithelial cells

Gebert

Bartoszewska

Janaszak-Jasiecka

et al. 2018

Sci Rep

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Small noncoding microRNAs (miRNAs) post-transcriptionally regulate a large portion of the human transcriptome. miRNAs have been shown to play an important role in the unfolded protein response (UPR), a cellular adaptive mechanism that is important in alleviating endoplasmic reticulum (ER) stress and promoting cell recovery. Another class of small noncoding RNAs, the Piwi-interacting RNAs (piRNAs) together with PIWI proteins, was originally shown to play a role as repressors of germline transposable elements. More recent studies, however, indicate that P-element induced WImpy proteins (PIWI proteins) and piRNAs also regulate mRNA levels in somatic tissues. Using genome-wide small RNA next generation sequencing, cell viability assays, and caspase activity assays in human airway epithelial cells, we demonstrate that ER stress specifically up-regulates total piRNA expression profiles, and these changes correlate with UPR-induced apoptosis as shown by up-regulation of two pro-apoptotic factor mRNAs, CHOP and NOXA. Furthermore, siRNA knockdown of PIWIL2 and PIWIL4, two proteins involved in piRNA function, attenuates UPR-related cell death, inhibits piRNA expression, and inhibits the up-regulation of CHOP and NOXA mRNA expression. Hence, we provide evidence that PIWIL2 and PIWIL4 proteins, and potentially the up-regulated piRNAs, constitute a novel epigenetic mechanism that control cellular fate during the UPR.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

PIWI proteins contribute to apoptosis during the UPR in human airway epithelial cells

Gebert

Bartoszewska

Janaszak-Jasiecka

et al. 2018

Sci Rep

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“…A particular pharmacological interest relies on the design of tailored enzymes with specific RNA cleavage targets (Tamkovich et al, 2016). Recent work on RNases’ action within a cellular environment is helping to unravel their natural in vivo substrates (Honda et al, 2015; Lyons et al, 2017; Mesitov et al, 2017). A proper knowledge of the RNases’ active site architecture should lead to the design of specific inhibitors of their biological functions (Chatzileontiadou et al, 2015; Chatzileontiadou et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Evolutionary Trends in RNA Base Selectivity Within the RNase A Superfamily

Prats-Ejarque

Salazar

et al. 2019

Front. Pharmacol.

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There is a growing interest in the pharmaceutical industry to design novel tailored drugs for RNA targeting. The vertebrate-specific RNase A superfamily is nowadays one of the best characterized family of enzymes and comprises proteins involved in host defense with specific cytotoxic and immune-modulatory properties. We observe within the family a structural variability at the substrate-binding site associated to a diversification of biological properties. In this work, we have analyzed the enzyme specificity at the secondary base binding site. Towards this end, we have performed a kinetic characterization of the canonical RNase types together with a molecular dynamic simulation of selected representative family members. The RNases’ catalytic activity and binding interactions have been compared using UpA, UpG and UpI dinucleotides. Our results highlight an evolutionary trend from lower to higher order vertebrates towards an enhanced discrimination power of selectivity for adenine respect to guanine at the secondary base binding site (B2). Interestingly, the shift from guanine to adenine preference is achieved in all the studied family members by equivalent residues through distinct interaction modes. We can identify specific polar and charged side chains that selectively interact with donor or acceptor purine groups. Overall, we observe selective bidentate polar and electrostatic interactions: Asn to N1/N6 and N6/N7 adenine groups in mammals versus Glu/Asp and Arg to N1/N2, N1/O6 and O6/N7 guanine groups in non-mammals. In addition, kinetic and molecular dynamics comparative results on UpG versus UpI emphasize the main contribution of Glu/Asp interactions to N1/N2 group for guanine selectivity in lower order vertebrates. A close inspection at the B2 binding pocket also highlights the principal contribution of the protein ß6 and L4 loop regions. Significant differences in the orientation and extension of the L4 loop could explain how the same residues can participate in alternative binding modes. The analysis suggests that within the RNase A superfamily an evolution pressure has taken place at the B2 secondary binding site to provide novel substrate-recognition patterns. We are confident that a better knowledge of the enzymes’ nucleotide recognition pattern would contribute to identify their physiological substrate and eventually design applied therapies to modulate their biological functions.

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“…5–7 Its protein maturation machinery and other energy-intensive processes make the ER highly sensitive to numerous factors, including toxins, nutrition, and energy deprivation, redox imbalances, and disorder in Ca 2+ storage. 8 …”

Section: Introductionmentioning

confidence: 99%

Acid-Sensing Ion Channel 1a Regulates Fate of Rat Nucleus Pulposus Cells in Acid Stimulus Through Endoplasmic Reticulum Stress

Xie

Chen

Zhang

et al. 2018

BioResearch Open Access

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Acid-sensing ion channel 1a (ASIC1a) participates in human intervertebral disc degeneration (IVDD) and regulates the destiny of nucleus pulposus cells (NPCs) in acid stimulus. However, the mechanism of ASIC1a activation and its downstream pathway remain unclear. Endoplasmic reticulum (ER) stress also participates in the acid-induced apoptosis of NPCs. The main purpose of this study was to investigate whether there is any connection between ASIC1a and ER stress in an acid-induced nucleus pulposus degeneration model. The IVDs of Sprague-Dawley rats were stained by immunohistochemical staining to evaluate the expression of ASIC1a in normal and degenerated rat nucleus pulposus. ASIC1a expression was also quantified by quantitative real-time-polymerase chain reaction and Western blotting analysis. NPCs were exposed to the culture media with acidity at pH 7.2 and 6.5 for 24 h, with or without 4-phenylbutyrate (4-PBA, a blocker of the ER stress pathway). Cell apoptosis was examined by Annexin V/Propidium Iodide (PI) staining and was quantified using flow cytometry analysis. ASIC1a-mediated intracellular calcium was determined by Ca2+ imaging using Fura-2-AM. Acidity-induced changes in ER stress markers were studied using Western blotting analysis. In vivo, ASIC1a expression was upregulated in natural degeneration. In vitro, acid stimulus increased intracellular calcium levels, but this effect was blocked by knockdown of ASIC1a, and this reversal was partly inhibited by 4-PBA. In addition, blockade of ASIC1a reduced expression of ER stress markers, especially the proapoptotic markers. ASIC1a partly regulates ER stress and promotes apoptosis of NPCs under acid stimulus and may be a novel therapeutic target in IVDD.

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Differential processing of small RNAs during endoplasmic reticulum stress

Cited by 22 publications

References 90 publications

PIWI proteins contribute to apoptosis during the UPR in human airway epithelial cells

PIWI proteins contribute to apoptosis during the UPR in human airway epithelial cells

Evolutionary Trends in RNA Base Selectivity Within the RNase A Superfamily

Acid-Sensing Ion Channel 1a Regulates Fate of Rat Nucleus Pulposus Cells in Acid Stimulus Through Endoplasmic Reticulum Stress

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