scholarly journals Non-canonical role of wild-type SEC23B in the cellular stress response pathway

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Lamis Yehia ◽  
Darren Liu ◽  
Shuai Fu ◽  
Pranav Iyer ◽  
Charis Eng
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Cell Biology ◽  
Ribosome Biogenesis ◽  
Cellular Stress ◽  
Cellular Stress Response ◽  
Wild Type ◽  
Protein Ubiquitination ◽  
Cytoplasmic Transport ◽  
Stress Response Pathway

AbstractWhile germline recessive loss-of-function mutations in SEC23B in humans cause a rare form of anaemia, heterozygous change-of-function mutations result in increased predisposition to cancer. SEC23B encodes SEC23 homologue B, a component of coat protein complex II (COPII), which canonically transports proteins from the endoplasmic reticulum (ER) to the Golgi. Despite the association of SEC23B with anaemia and cancer, the precise pathophysiology of these phenotypic outcomes remains unknown. Recently, we reported that mutant SEC23B has non-canonical COPII-independent function, particularly within the ER stress and ribosome biogenesis pathways, and that may contribute to the pathobiology of cancer predisposition. In this study, we hypothesized that wild-type SEC23B has a baseline function within such cellular stress response pathways, with the mutant protein reflecting exaggerated effects. Here, we show that the wild-type SEC23B protein localizes to the nucleus in addition to classical distribution at the ER/Golgi interface and identify multiple putative nuclear localization and export signals regulating nuclear–cytoplasmic transport. Unexpectedly, we show that, independently of COPII, wild-type SEC23B can also localize to cell nucleoli under proteasome inhibition conditions, with distinct distribution patterns compared to mutant cells. Unbiased proteomic analyses through mass spectrometry further revealed that wild-type SEC23B interacts with a subset of nuclear proteins, in addition to central proteins in the ER stress, protein ubiquitination, and EIF2 signalling pathways. We validate the genotype-specific differential SEC23B–UBA52 (ribosomal protein RPL40) interaction. Finally, utilizing patient-derived lymphoblastoid cell lines harbouring either wild-type or mutant SEC23B, we show that SEC23B levels increase in response to ER stress, further corroborating its role as a cellular stress response sensor and/or effector. Overall, these observations suggest that SEC23B, irrespective of mutation status, has unexplored roles in the cellular stress response pathway, with implications relevant to cancer and beyond that, CDAII and normal cell biology.

The Leukemia-Associated Protein BTG1 Is Required for ATF4-Mediated Cellular Stress Responses

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3587-3587
Author(s):  
Laurensia Yuniati ◽  
Laurens T van der Meer ◽  
Geert JV Poelmans ◽  
Sander AL Palit ◽  
Caroline Rodenbach ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
B Cell ◽  
Cell Survival ◽  
Nutrient Limitation ◽  
Metabolic Activity ◽  
Target Genes ◽  
Cellular Stress ◽  
Cellular Stress Response ◽  
Average Data

Abstract During the course of tumorigenesis and subsequent chemotherapeutic intervention, cancer cells experience various kinds of physiological stress, including hypoxia and nutrient limitation. Escaping cell death is one of the routes utilized by these malignant cells to allow continued growth and to acquire therapy resistance. B-cell Translocation Gene 1 (BTG1) is recurrently affected by genomic deletion in pediatric acute lymphoblastic leukemia (ALL) patients. Here, we define BTG1 as a mediator of the cellular stress response. When challenged with cellular stressors, such as amino acid or glucose deprivation as well as drug induced Endoplasmic Reticulum (ER) stress, mouse embryonic fibroblasts (MEFs) lacking Btg1 expression show a 20-30% increased survival rate relative to wildtype cells (Figure 1). Similarly, bone marrow B-cell progenitors isolated from Btg1 knockout mice are more resistant to Asparaginase (ASNase), a drug widely used in the treatment of ALL. Activating Transcription Factor 4 (ATF4) is the master regulator of the stress response pathway that is activated upon nutrient limitation and ER stress. Importantly, loss of ATF4 function results in an enhanced survival almost identical to the effects we measured in Btg1 knockout cells. While ATF4 protein expression itself is not different between the genotypes, gene expression analysis revealed that the induction of a subset of ATF4 target genes (Ddit3, Atf3, Trib3, Gadd34, and Ndrg1) is significantly reduced in Btg1 knockout cells. As these genes are effectors of the apoptosis machinery, increased survival in the Btg1 knockout cells may reflect an attenuation of ATF4 function. We hypothesized that BTG1 complexes with ATF4 to modify its function by recruiting Protein Arginine Methyl Transferase 1 (PRMT1). This enzyme, known to cooperate with BTG1, marks its substrate proteins with a post translational modification but has not been previously implicated in the regulation of ATF4 activity. Co-immunoprecipitation experiments indeed revealed a direct interaction between BTG1 and ATF4. We used purified proteins in an in vitro methylation assay to show that ATF4 is directly methylated by PRMT1 on arginine residue 239. Expression of the mutant ATF4 R239K, which cannot be methylated, in an ATF4 knockout background resulted in reduced transcriptional activity in response to stress relative to wildtype ATF4. In addition, we aimed to mimic the effect of BTG1 loss on the regulation ATF4 function by the addition of PRMT1 inhibitor AMI-1. Treatment of cells with this selective inhibitor faithfully recapitulates BTG1 loss by attenuating the induction of ATF4 target genes upon stress. Our findings establish the interplay of BTG1-ATF4-PRMT1 as a part of the cellular stress response. Taken together, our data indicate that BTG1 is necessary to maintain normal ATF4 function under cellular stress conditions. Loss of BTG1 expression, as it occurs during lymphoid leukemia development, may therefore provide a selective advantage for leukemic cells to survive and to resist treatment at a later stage of disease. Figure 1 Btg1 is required for survival under cellular stress. Wildtype (WT) and Btg1-/- MEFs were challenged with different treatments that cause nutrient limitation and ER stress. A MTT based assay was used to study the metabolic activity of the cells as a measure of viability. The relative cell survival as compared to untreated cells (set as 100%) is shown. Bars represent average data from four independent experiments ± SEM. 2-tailed t-test was used to test for significance: * p<0.05, ** p<0.01. Figure 1. Btg1 is required for survival under cellular stress. Wildtype (WT) and Btg1-/- MEFs were challenged with different treatments that cause nutrient limitation and ER stress. A MTT based assay was used to study the metabolic activity of the cells as a measure of viability. The relative cell survival as compared to untreated cells (set as 100%) is shown. Bars represent average data from four independent experiments ± SEM. 2-tailed t-test was used to test for significance: * p<0.05, ** p<0.01. Disclosures No relevant conflicts of interest to declare.

scholarly journals Gold Nanoparticles Impinge on Nucleoli and the Stress Response in MCF7 Breast Cancer Cells

10.5772/62337 ◽  
2016 ◽  
Vol 3 ◽  
pp. 3 ◽  
Author(s):  
Mohamed Kodiha ◽  
Hicham Mahboubi ◽  
Dusica Maysinger ◽  
Ursula Stochaj
Keyword(s):  
Gold Nanoparticles ◽  
Stress Response ◽  
Cancer Cells ◽  
Ribosome Biogenesis ◽  
Cellular Stress ◽  
Cellular Stress Response ◽  
Cellular Functions ◽  
Gold Nanoflowers ◽  
Underlying Mechanisms ◽  
And Function

Cancer cells can take up gold nanoparticles of different morphologies. These particles interact with the plasma membrane and often travel to intracellular organelles. Among organelles, the nucleus is especially susceptible to the damage that is inflicted by gold nanoparticles. Located inside the nucleus, nucleoli are specialized compartments that transcribe ribosomal RNA genes, produce ribosomes and function as cellular stress sensors. Nucleoli are particularly prone to gold nanoparticle-induced injury. As such, small spherical gold nanoparticles and gold nanoflowers interfere with the transcription of ribosomal DNA. However, the underlying mechanisms are not fully understood. In this study, we examined the effects of gold nanoparticles on nucleolar proteins that are critical to ribosome biogenesis and other cellular functions. We show that B23/nucleophosmin, a nucleolar protein that is tightly linked to cancer, is significantly affected by gold nanoparticles. Furthermore, gold nanoparticles impinge on the cellular stress response, as they reduce the abundance of the molecular chaperone hsp70 and O-GlcNAc modified proteins in the nucleus and nucleoli. Together, our studies set the stage for the development of nanomedicines that target the nucleolus to eradicate proliferating cancer cells.

scholarly journals Flavonoids: Potential Candidates for the Treatment of Neurodegenerative Disorders

Biomedicines ◽  
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.

scholarly journals Mitochondrien unter Stress: Die Rolle der Präsequenzprotease MPP

BIOspektrum ◽  
2021 ◽  
Vol 27 (4) ◽  
pp. 390-393
Author(s):  
F.-Nora Vögtle
Keyword(s):  
Stress Response ◽  
Cellular Stress ◽  
Critical Role ◽  
Mitochondrial Protein ◽  
Nuclear Genome ◽  
Cellular Stress Response ◽  
Mitochondrial Proteins ◽  
Protein Biogenesis ◽  
Cellular Integrity

AbstractThe majority of mitochondrial proteins are encoded in the nuclear genome, so that the nearly entire proteome is assembled by post-translational preprotein import from the cytosol. Proteomic imbalances are sensed and induce cellular stress response pathways to restore proteostasis. Here, the mitochondrial presequence protease MPP serves as example to illustrate the critical role of mitochondrial protein biogenesis and proteostasis on cellular integrity.

scholarly journals m5U54 tRNA Hypomodification by Lack of TRMT2A Drives the Generation of tRNA-Derived Small RNAs

2021 ◽  
Vol 22 (6) ◽  
pp. 2941
Author(s):  
Marisa Pereira ◽  
Diana R. Ribeiro ◽  
Miguel M. Pinheiro ◽  
Margarida Ferreira ◽  
Stefanie Kellner ◽  
...  
Keyword(s):  
Stress Response ◽  
Small Rnas ◽  
Mammalian Cells ◽  
Cellular Stress ◽  
Cellular Stress Response ◽  
Translation Regulation ◽  
Translation Efficiency ◽  
Down Regulation ◽  
Gene Expression Control ◽  
The Impact

Transfer RNA (tRNA) molecules contain various post-transcriptional modifications that are crucial for tRNA stability, translation efficiency, and fidelity. Besides their canonical roles in translation, tRNAs also originate tRNA-derived small RNAs (tsRNAs), a class of small non-coding RNAs with regulatory functions ranging from translation regulation to gene expression control and cellular stress response. Recent evidence indicates that tsRNAs are also modified, however, the impact of tRNA epitranscriptome deregulation on tsRNAs generation is only now beginning to be uncovered. The 5-methyluridine (m5U) modification at position 54 of cytosolic tRNAs is one of the most common and conserved tRNA modifications among species. The tRNA methyltransferase TRMT2A catalyzes this modification, but its biological role remains mostly unexplored. Here, we show that TRMT2A knockdown in human cells induces m5U54 tRNA hypomodification and tsRNA formation. More specifically, m5U54 hypomodification is followed by overexpression of the ribonuclease angiogenin (ANG) that cleaves tRNAs near the anticodon, resulting in accumulation of 5′tRNA-derived stress-induced RNAs (5′tiRNAs), namely 5′tiRNA-GlyGCC and 5′tiRNA-GluCTC, among others. Additionally, transcriptomic analysis confirms that down-regulation of TRMT2A and consequently m5U54 hypomodification impacts the cellular stress response and RNA stability, which is often correlated with tiRNA generation. Accordingly, exposure to oxidative stress conditions induces TRMT2A down-regulation and tiRNA formation in mammalian cells. These results establish a link between tRNA hypomethylation and ANG-dependent tsRNAs formation and unravel m5U54 as a tRNA cleavage protective mark.

scholarly journals C. elegans discriminates colors to guide foraging

Science ◽  
2021 ◽  
Vol 371 (6533) ◽  
pp. 1059-1063 ◽  
Author(s):  
D. Dipon Ghosh ◽  
Dongyeop Lee ◽  
Xin Jin ◽  
H. Robert Horvitz ◽  
Michael N. Nitabach
Keyword(s):  
Stress Response ◽  
Cellular Stress ◽  
Color Discrimination ◽  
Cellular Stress Response ◽  
Blue Pigment ◽  
Natural Environments ◽  
C Elegans ◽  
Evolutionarily Conserved ◽  
Foraging Decisions ◽  
Light Guides

Color detection is used by animals of diverse phyla to navigate colorful natural environments and is thought to require evolutionarily conserved opsin photoreceptor genes. We report that Caenorhabditis elegans roundworms can discriminate between colors despite the fact that they lack eyes and opsins. Specifically, we found that white light guides C. elegans foraging decisions away from a blue-pigment toxin secreted by harmful bacteria. These foraging decisions are guided by specific blue-to-amber ratios of light. The color specificity of color-dependent foraging varies notably among wild C. elegans strains, which indicates that color discrimination is ecologically important. We identified two evolutionarily conserved cellular stress response genes required for opsin-independent, color-dependent foraging by C. elegans, and we speculate that cellular stress response pathways can mediate spectral discrimination by photosensitive cells and organisms—even by those lacking opsins.

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