Distinct stress-dependent signatures of cellular and extracellular tRNA-derived small RNAs (tDRs)

The cellular response to stress is an important determinant of disease pathogenesis. Uncovering the molecular fingerprints of distinct stress responses may yield novel biomarkers for different diseases, and potentially identify key signaling pathways important for disease progression. tRNAs and tRNA-derived small RNAs (tDRs) comprise one of the most abundant RNA species in cells and have been associated with cellular stress responses. The presence of RNA modifications on tDRs has been an obstacle for accurately identifying tDRs with conventional small RNA sequencing. Here, we use AlkB-facilitated methylation sequencing (ARM-seq) to uncover a comprehensive landscape of cellular and extracellular tDR expression in a variety of human and rat cells during common stress responses, including nutritional deprivation, hypoxia, and oxidative stress. We found that extracellular tDRs have a distinct fragmentation signature with a predominant length of 31-33 nts and a highly specific termination position when compared with intracellular tDRs. Importantly, we found these signatures are better discriminators of different cellular stress responses compared to extracellular miRNAs. Distinct extracellular tDR signatures for each profiled stressor are elucidated in four different types of cells. This distinct extracellular tDR fragmentation pattern is also noted in plasma extracellular RNAs from patients on cardiopulmonary bypass. The observed overlap of these patient tDR signatures with the signatures of nutritional deprivation and oxidative stress in our cellular models provides preliminary in vivo corroboration of our findings and demonstrates the potential to establish novel extracellular tDR biomarkers in human disease models.

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The RNA helicase Ded1 regulates translation and granule formation during multiple phases of cellular stress responses

Molecular and Cellular Biology ◽

10.1128/mcb.00244-21 ◽

2021 ◽

Author(s):

Peyman P. Aryanpur ◽

Telsa M. Mittelmeier ◽

Timothy A. Bolger

Keyword(s):

Oxidative Stress ◽

Stress Responses ◽

Cellular Stress ◽

Low Complexity ◽

Rna Helicase ◽

Additional Contribution ◽

Granule Formation ◽

Growth Defects ◽

Cellular Stress Responses ◽

And Oxidative Stress

Ded1 is a conserved RNA helicase that promotes translation initiation in steady-state conditions. Ded1 has also been shown to regulate translation during cellular stress and affect the dynamics of stress granules (SGs), accumulations of RNA and protein linked to translation repression. To better understand its role in stress responses, we examined Ded1 function in two different models: DED1 overexpression and oxidative stress. DED1 overexpression inhibits growth and promotes the formation of SGs. A ded1 mutant lacking the low-complexity C-terminal region ( ded1-ΔCT ), which mediates Ded1 oligomerization and interaction with the translation factor eIF4G1, suppressed these phenotypes, consistent with other stresses. During oxidative stress, a ded1-ΔCT mutant was defective in growth and in SG formation compared to wild-type cells, although SGs were increased rather than decreased in these conditions. Unlike stress induced by direct TOR inhibition, the phenotypes in both models were only partially dependent on eIF4G1 interaction, suggesting an additional contribution from Ded1 oligomerization. Furthermore, examination of the growth defects and translational changes during oxidative stress suggested that Ded1 plays a role during recovery from stress. Integrating these disparate results, we propose that Ded1 controls multiple aspects of translation and RNP dynamics in both initial stress responses and during recovery.

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The RNA helicase Ded1 regulates translation and granule formation during multiple phases of cellular stress responses

10.1101/2021.06.02.446858 ◽

2021 ◽

Author(s):

Peyman P Aryanpur ◽

Telsa M. Mittelmeier ◽

Timothy A Bolger

Keyword(s):

Oxidative Stress ◽

Stress Responses ◽

Cellular Stress ◽

Low Complexity ◽

Rna Helicase ◽

Additional Contribution ◽

Granule Formation ◽

Growth Defects ◽

Cellular Stress Responses ◽

And Oxidative Stress

Ded1 is a conserved RNA helicase that promotes translation initiation in steady-state conditions. Ded1 has also been shown to regulate translation during cellular stress and affect the dynamics of stress granules (SGs), accumulations of RNA and protein linked to translation repression. To better understand its role in stress responses, we examined Ded1 function in two different models: DED1 overexpression and oxidative stress. DED1 overexpression inhibits growth and promotes the formation of SGs. A ded1 mutant lacking the low-complexity C-terminal region (ded1-ΔCT), which mediates Ded1 oligomerization and interaction with the translation factor eIF4G, suppressed these phenotypes, consistent with other stresses. During oxidative stress, a ded1-ΔCT mutant was defective in growth and in SG formation compared to wild-type cells, although SGs were increased rather than decreased in these conditions. Unlike stress induced by direct TOR inhibition, the phenotypes in both models were only partially dependent on eIF4G interaction, suggesting an additional contribution from Ded1 oligomerization. Furthermore, examination of the growth defects and translational changes during oxidative stress suggested that Ded1 plays a role during recovery from stress. Integrating these disparate results, we propose that Ded1 controls multiple aspects of translation and RNP dynamics in both initial stress responses and during recovery.

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Global transcriptomic profiling demonstrates induction of oxidative stress and of compensatory cellular stress responses in brown trout exposed to glyphosate and Roundup

BMC Genomics ◽

10.1186/s12864-015-1254-5 ◽

2015 ◽

Vol 16 (1) ◽

Cited By ~ 52

Author(s):

Tamsyn M Uren Webster ◽

Eduarda M Santos

Keyword(s):

Oxidative Stress ◽

Brown Trout ◽

Stress Responses ◽

Cellular Stress ◽

Transcriptomic Profiling ◽

Cellular Stress Responses

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PARP-1 activation after oxidative insult promotes energy stress-dependent phosphorylation of YAP1 and reduces cell viability

Biochemical Journal ◽

10.1042/bcj20200525 ◽

2020 ◽

Vol 477 (23) ◽

pp. 4491-4513

Author(s):

Sandra M. Martín-Guerrero ◽

Pedro Casado ◽

Maruan Hijazi ◽

Vinothini Rajeeve ◽

Julio Plaza-Díaz ◽

...

Keyword(s):

Oxidative Stress ◽

Oxidative Damage ◽

Cell Viability ◽

Stress Responses ◽

H2o2 Treatment ◽

Oxidative Treatment ◽

Energy Stress ◽

Cellular Stress Responses ◽

Stress Dependent ◽

Parp 1

Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that catalyze the transfer of ADP-ribose units from NAD+ to several target proteins involved in cellular stress responses. Using WRL68 (HeLa derivate) cells, we previously showed that PARP-1 activation induced by oxidative stress after H2O2 treatment lead to depletion of cellular NAD+ and ATP, which promoted cell death. In this work, LC–MS/MS-based phosphoproteomics in WRL68 cells showed that the oxidative damage induced by H2O2 increased the phosphorylation of YAP1, a transcriptional co-activator involved in cell survival, and modified the phosphorylation of other proteins involved in transcription. Genetic or pharmacological inhibition of PARP-1 in H2O2-treated cells reduced YAP1 phosphorylation and degradation and increased cell viability. YAP1 silencing abrogated the protective effect of PARP-1 inhibition, indicating that YAP1 is important for the survival of WRL68 cells exposed to oxidative damage. Supplementation of NAD+ also reduced YAP1 phosphorylation, suggesting that the loss of cellular NAD+ caused by PARP-1 activation after oxidative treatment is responsible for the phosphorylation of YAP1. Finally, PARP-1 silencing after oxidative treatment diminished the activation of the metabolic sensor AMPK. Since NAD+ supplementation reduced the phosphorylation of some AMPK substrates, we hypothesized that the loss of cellular NAD+ after PARP-1 activation may induce an energy stress that activates AMPK. In summary, we showed a new crucial role of PARP-1 in the response to oxidative stress in which PARP-1 activation reduced cell viability by promoting the phosphorylation and degradation of YAP1 through a mechanism that involves the depletion of NAD+.

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Cellular Stress Responses and Gut Microbiota in Inflammatory Bowel Disease

Gastroenterology Research and Practice ◽

10.1155/2018/7192646 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 8

Author(s):

Siyan “Stewart” Cao

Keyword(s):

Oxidative Stress ◽

Inflammatory Bowel Disease ◽

Gut Microbiota ◽

Er Stress ◽

Stress Responses ◽

Bowel Disease ◽

Cellular Stress ◽

Cellular Stress Responses ◽

Inflammatory Bowel ◽

Stress Oxidative

Progresses in the past two decades have greatly expanded our understanding of inflammatory bowel disease (IBD), an incurable disease with multifaceted and challenging clinical manifestations. The pathogenesis of IBD involves multiple processes on the cellular level, which include the stress response signaling such as endoplasmic reticulum (ER) stress, oxidative stress, and hypoxia. Under physiological conditions, the stress responses play key roles in cell survival, mucosal barrier integrity, and immunomodulation. However, they can also cause energy depletion, trigger cell death and tissue injury, promote inflammatory response, and drive the progression of clinical disease. In recent years, gut microflora has emerged as an essential pathogenic factor and therapeutic target for IBD. Altered compositional and metabolic profiles of gut microbiota, termed dysbiosis, are associated with IBD. Recent studies, although limited, have shed light on how ER stress, oxidative stress, and hypoxic stress interact with gut microorganisms, a potential source of stress in the microenvironment of gastrointestinal tract. Our knowledge of cellular stress responses in intestinal homeostasis as well as their cross-talks with gut microbiome will further our understanding of the pathogenesis of inflammatory bowel disease and probably open avenues for new therapies.

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Repressive effect of Rhus coriaria L. fruit extracts on microglial cells-mediated inflammatory and oxidative stress responses

Journal of Ethnopharmacology ◽

10.1016/j.jep.2020.113748 ◽

2021 ◽

Vol 269 ◽

pp. 113748

Author(s):

Mohamad Khalil ◽

Ali Bazzi ◽

Dana Zeineddine ◽

Wissam Jomaa ◽

Ahmad Daher ◽

...

Keyword(s):

Oxidative Stress ◽

Stress Responses ◽

Microglial Cells ◽

Fruit Extracts ◽

Repressive Effect ◽

Rhus Coriaria ◽

Oxidative Stress Responses ◽

And Oxidative Stress

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Flavonoids: Potential Candidates for the Treatment of Neurodegenerative Disorders

Biomedicines ◽

10.3390/biomedicines9020099 ◽

2021 ◽

Vol 9 (2) ◽

pp. 99

Author(s):

Shweta Devi ◽

Vijay Kumar ◽

Sandeep Kumar Singh ◽

Ashish Kant Dubey ◽

Jong-Joo Kim

Keyword(s):

Stress Response ◽

Stress Responses ◽

Neurodegenerative Disorders ◽

Cell Damage ◽

Cellular Stress ◽

Clinical Manifestations ◽

Cellular Stress Response ◽

Dramatic Rise ◽

Cellular Stress Responses

Neurodegenerative disorders, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), are the most concerning disorders due to the lack of effective therapy and dramatic rise in affected cases. Although these disorders have diverse clinical manifestations, they all share a common cellular stress response. These cellular stress responses including neuroinflammation, oxidative stress, proteotoxicity, and endoplasmic reticulum (ER)-stress, which combats with stress conditions. Environmental stress/toxicity weakened the cellular stress response which results in cell damage. Small molecules, such as flavonoids, could reduce cellular stress and have gained much attention in recent years. Evidence has shown the potential use of flavonoids in several ways, such as antioxidants, anti-inflammatory, and anti-apoptotic, yet their mechanism is still elusive. This review provides an insight into the potential role of flavonoids against cellular stress response that prevent the pathogenesis of neurodegenerative disorders.

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Crosstalk between endoplasmic reticulum stress and oxidative stress: a dynamic duo in multiple myeloma

Cellular and Molecular Life Sciences ◽

10.1007/s00018-021-03756-3 ◽

2021 ◽

Author(s):

Sinan Xiong ◽

Wee-Joo Chng ◽

Jianbiao Zhou

Keyword(s):

Oxidative Stress ◽

Multiple Myeloma ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Cell Fate ◽

Stress Responses ◽

Plasma Cells ◽

Reactive Oxygen Species Generation ◽

Future Research ◽

And Oxidative Stress

AbstractUnder physiological and pathological conditions, cells activate the unfolded protein response (UPR) to deal with the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum. Multiple myeloma (MM) is a hematological malignancy arising from immunoglobulin-secreting plasma cells. MM cells are subject to continual ER stress and highly dependent on the UPR signaling activation due to overproduction of paraproteins. Mounting evidence suggests the close linkage between ER stress and oxidative stress, demonstrated by overlapping signaling pathways and inter-organelle communication pivotal to cell fate decision. Imbalance of intracellular homeostasis can lead to deranged control of cellular functions and engage apoptosis due to mutual activation between ER stress and reactive oxygen species generation through a self-perpetuating cycle. Here, we present accumulating evidence showing the interactive roles of redox homeostasis and proteostasis in MM pathogenesis and drug resistance, which would be helpful in elucidating the still underdefined molecular pathways linking ER stress and oxidative stress in MM. Lastly, we highlight future research directions in the development of anti-myeloma therapy, focusing particularly on targeting redox signaling and ER stress responses.

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