scholarly journals Zinc transporter ZIP7 is a novel determinant of ferroptosis

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Po-Han Chen ◽  
Jianli Wu ◽  
Yitong Xu ◽  
Chien-Kuang Cornelia Ding ◽  
Alexander A. Mestre ◽  
...  
Keyword(s):  
Iron Chelation ◽  
Death Process ◽  
Therapeutic Implications ◽  
Oxidative Stresses ◽  
Regulated Cell Death ◽  
A Genome ◽  
Zinc Addition ◽  
Zinc Chelator ◽  
Chemical Inhibition ◽  
Er Homeostasis

AbstractFerroptosis is a newly described form of regulated cell death triggered by oxidative stresses and characterized by extensive lipid peroxidation and membrane damages. The name of ferroptosis indicates that the ferroptotic death process depends on iron, but not other metals, as one of its canonical features. Here, we reported that zinc is also essential for ferroptosis in breast and renal cancer cells. Zinc chelator suppressed ferroptosis, and zinc addition promoted ferroptosis, even during iron chelation. By interrogating zinc-related genes in a genome-wide RNAi screen of ferroptosis, we identified SLC39A7, encoding ZIP7 that controls zinc transport from endoplasmic reticulum (ER) to cytosol, as a novel genetic determinant of ferroptosis. Genetic and chemical inhibition of the ZIP7 protected cells against ferroptosis, and the ferroptosis protection upon ZIP7 knockdown can be abolished by zinc supplementation. We found that the genetic and chemical inhibition of ZIP7 triggered ER stresses, including the induction of the expression of HERPUD1 and ATF3. Importantly, the knockdown of HERPUD1 abolished the ferroptosis protection phenotypes of ZIP7 inhibition. Together, we have uncovered an unexpected role of ZIP7 in ferroptosis by maintaining ER homeostasis. These findings may have therapeutic implications for human diseases involving ferroptosis and zinc dysregulations.

scholarly journals Ferrous-glutathione coupling mediates ferroptosis and frailty in Caenorhabditis elegans

2019 ◽  
Author(s):  
Nicole L. Jenkins ◽  
Simon A. James ◽  
Agus Salim ◽  
Fransisca Sumardy ◽  
Terence P. Speed ◽  
...  
Keyword(s):  
Cell Death ◽  
Caenorhabditis Elegans ◽  
Ferrous Iron ◽  
Somatic Tissue ◽  
Glutathione Depletion ◽  
Death Process ◽  
C Elegans ◽  
Regulated Cell Death ◽  
Age Related ◽  
Ageing Rate

All eukaryotes require iron. Replication, detoxification, and a cancer-protective form of regulated cell death termed ferroptosis1, all depend on iron metabolism. Ferrous iron accumulates over adult lifetime in the Caenorhabditis elegans model of ageing2. Here we show that glutathione depletion is coupled to ferrous iron elevation in these animals, and that both occur in late life to prime cells for ferroptosis. We demonstrate that blocking ferroptosis, either by inhibition of lipid peroxidation or by limiting iron retention, mitigates age-related cell death and markedly increases lifespan and healthspan in C. elegans. Temporal scaling of lifespan is not evident when ferroptosis is inhibited, consistent with this cell death process acting at specific life phases to induce organismal frailty, rather than contributing to a constant ageing rate. Because excess age-related iron elevation in somatic tissue, particularly in brain3–5, is thought to contribute to degenerative disease6, 7, our data indicate that post-developmental interventions to limit ferroptosis may promote healthy ageing.

scholarly journals A Genome Scale Screen for Mutants with Delayed Exit from Mitosis: Ire1-Independent Induction of Autophagy Integrates ER Homeostasis into Mitotic Lifespan

PLoS Genetics ◽  
2015 ◽  
Vol 11 (8) ◽  
pp. e1005429 ◽  
Author(s):  
Ata Ghavidel ◽  
Kunal Baxi ◽  
Vladimir Ignatchenko ◽  
Martin Prusinkiewicz ◽  
Terra G. Arnason ◽  
...  
Keyword(s):  
A Genome ◽  
Genome Scale ◽  
Er Homeostasis

scholarly journals Changes in ferrous iron and glutathione promote ferroptosis and frailty in aging Caenorhabditis elegans

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Nicole L Jenkins ◽  
Simon A James ◽  
Agus Salim ◽  
Fransisca Sumardy ◽  
Terence P Speed ◽  
...  
Keyword(s):  
Cell Death ◽  
Caenorhabditis Elegans ◽  
Ferrous Iron ◽  
Healthy Aging ◽  
Somatic Tissue ◽  
Glutathione Depletion ◽  
Death Process ◽  
Regulated Cell Death ◽  
Age Related ◽  
Cell Death Process

All eukaryotes require iron. Replication, detoxification, and a cancer-protective form of regulated cell death termed ferroptosis, all depend on iron metabolism. Ferrous iron accumulates over adult lifetime in Caenorhabditis elegans. Here, we show that glutathione depletion is coupled to ferrous iron elevation in these animals, and that both occur in late life to prime cells for ferroptosis. We demonstrate that blocking ferroptosis, either by inhibition of lipid peroxidation or by limiting iron retention, mitigates age-related cell death and markedly increases lifespan and healthspan. Temporal scaling of lifespan is not evident when ferroptosis is inhibited, consistent with this cell death process acting at specific life phases to induce organismal frailty, rather than contributing to a constant aging rate. Because excess age-related iron elevation in somatic tissue, particularly in brain, is thought to contribute to degenerative disease, post-developmental interventions to limit ferroptosis may promote healthy aging.

scholarly journals Dysregulation of alternative splicing is associated with the pathogenesis of ulcerative colitis

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Daowei Li ◽  
Yue Tan
Keyword(s):  
Ulcerative Colitis ◽  
Alternative Splicing ◽  
Tissue Samples ◽  
Therapeutic Implications ◽  
Aberrant Gene Expression ◽  
Genome Wide ◽  
Genomic Landscape ◽  
A Genome ◽  
Post Transcriptional Regulation ◽  
Aberrant Gene

Abstract Background Although numerous risk loci for ulcerative colitis (UC) have been identified in the human genome, the pathogenesis of UC remains unclear. Recently, multiple transcriptomic analyses have shown that aberrant gene expression in the colon tissues of UC patients is associated with disease progression. A pioneering study also demonstrated that altered post-transcriptional regulation is involved in the progression of UC. Here, we provide a genome-wide analysis of alternative splicing (AS) signatures in UC patients. We analyzed three datasets containing 74 tissue samples from UC patients and identified over 2000 significant AS events. Results Skipped exon and alternative first exon were the two most significantly altered AS events in UC patients. The immune response-related pathways were remarkably enriched in the UC-related AS events. Genes with significant AS events were more likely to be dysregulated at the expression level. Conclusions We present a genomic landscape of AS events in UC patients based on a combined analysis of two cohorts. Our results indicate that dysregulation of AS may have a pivotal role in determining the pathogenesis of UC. In addition, our study uncovers genes with potential therapeutic implications for UC treatment.

scholarly journals Regulation of Cell Death Induced by Acetic Acid in Yeasts

2021 ◽  
Vol 9 ◽  
Author(s):  
Susana R. Chaves ◽  
António Rego ◽  
Vítor M. Martins ◽  
Cátia Santos-Pereira ◽  
Maria João Sousa ◽  
...  
Keyword(s):  
Cell Death ◽  
Acetic Acid ◽  
Genetic Regulation ◽  
Industrial Applications ◽  
Research Field ◽  
Yeast Cells ◽  
Death Process ◽  
Regulated Cell Death ◽  
Molecular Events ◽  
The Impact

Acetic acid has long been considered a molecule of great interest in the yeast research field. It is mostly recognized as a by-product of alcoholic fermentation or as a product of the metabolism of acetic and lactic acid bacteria, as well as of lignocellulosic biomass pretreatment. High acetic acid levels are commonly associated with arrested fermentations or with utilization as vinegar in the food industry. Due to its obvious interest to industrial processes, research on the mechanisms underlying the impact of acetic acid in yeast cells has been increasing. In the past twenty years, a plethora of studies have addressed the intricate cascade of molecular events involved in cell death induced by acetic acid, which is now considered a model in the yeast regulated cell death field. As such, understanding how acetic acid modulates cellular functions brought about important knowledge on modulable targets not only in biotechnology but also in biomedicine. Here, we performed a comprehensive literature review to compile information from published studies performed with lethal concentrations of acetic acid, which shed light on regulated cell death mechanisms. We present an historical retrospective of research on this topic, first providing an overview of the cell death process induced by acetic acid, including functional and structural alterations, followed by an in-depth description of its pharmacological and genetic regulation. As the mechanistic understanding of regulated cell death is crucial both to design improved biomedical strategies and to develop more robust and resilient yeast strains for industrial applications, acetic acid-induced cell death remains a fruitful and open field of study.

A Genome Wide shRNA Screen In Primary Human AML Cells Identifies ROCK1 As a Novel Therapeutic Target

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 170-170
Author(s):  
Martin Wermke ◽  
Aylin Camgoz ◽  
Maciej Paszkowski-Rogacz ◽  
Sebastian Thieme ◽  
Malte von Bonin ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Therapeutic Targets ◽  
Host Cells ◽  
Leukemic Cells ◽  
Therapeutic Implications ◽  
Genome Wide ◽  
A Genome ◽  
Shrna Library ◽  
Shrna Screen ◽  
Novel Therapeutic

Abstract In spite of recent advances, the prognosis especially of elderly AML patients remains unsatisfactory with survival rates of less than 10 % at 10 years. Genome-wide RNA-interference screens systematically interrogating the specific vulnerabilities of leukemic cells could be a valuable tool to identify novel therapeutic targets in this patient population. So far, such screens have only been done in immortalized cell lines and / or at sub-genome scale, which limits their transferability to individual patients. Therefore, we set out to establish an unbiased genome-wide pooled shRNA screen in primary human AML cells to prove the feasibility and test the possible clinical implications of such an approach. Lentiviral transduction of primary leukemic blasts from a 67-year old patient with AML FAB M1 with a pooled shRNA library (Mission TRC shRNA library SP1, Sigma) according to a specifically optimized protocol resulted in a transduction rate of 25 %, thus rendering multiple integrants unlikely. An aliquot of the cells was separated for DNA extraction directly after removal of viral supernatant (day 0) and after 9 days of suspension culture (day 9). ShRNA barcodes integrated into the genome of the host cells were read out using PCR-coupled next-generation sequencing (HiSeq 2000, Illumina). Of 7709 shRNA contained in the library, 6626 were recovered with at least 10 reads in the day 0 sample. After 9 days of culture, 25 shRNA targeting a total of 12 genes were identified as potentially lethal to the patient's AML-cells (Table 1). All of these shRNA were subjected to single-shRNA transduction experiments using leukemic cells from the same donor. In fact, 18 of 25 shRNA were validated with respect to viability. Knockdown specificity was documented for all validated shRNA by qPCR. For further analyses we focused only on those 7 genes in which more than 50% of the shRNA identified in the pooled screen could be validated (Table 1). These genes were assessed for druggability using publicly available databases. For exploration of the potential therapeutic implications of our screen we chose ROCK1 as a potential target, because Fasudil, a specific ROCK1 inhibitor, has already been licensed for the treatment of pulmonary hypertension in humans.Table.Table1No. shRNAs >100 reads day 0No. scoring shRNA in pooled screenNo. valdiated shRNA in single shRNA experimentsOverall gene validation statusBNIPL322ValidatedC7orf16322ValidatedCCRL1321Not validatedDGAT2321Not validatedDUSP14320Not validatedMAP3K6422ValidatedROCK1532ValidatedRPS13322ValidatedSF3A1321Not validatedSNX27422ValidatedSTK3422ValidatedWDHD1220Not validated Knockdown of ROCK1 in primary leukemic blasts led to rapid cell-cycle arrest and cell-death. Treatment with Fasudil proved to be equally effective in killing leukemic cells. Compared to primary leukemic cells from the original as well as from other AML patients, Fasudil seemed to be less toxic to hematopoietic cells derived from healthy volunteer donors. RNA-sequencing revealed that in comparison to the healthy controls none of the studied AML patients demonstrated a significant overexpression of ROCK1. Moreover there was no indication for a functional ROCK1 mutation in the analyzed AML samples. Feeder based long-term culture initiating cell (LTC-IC) assays further suggested that Fasudil had a significant negative effect on the self-renewal capacity of primary human leukemic stem/progenitor cells (Figure 1). Studies in xenograft-models to assess the stem cell toxicity of ROCK1 inhibition in more detail are currently ongoing.Figure.Figure. Taken together our results show that pooled shRNA screens in primary patient-derived leukemic cells are feasible and able to pinpoint novel therapeutic targets, which might be missed in mutation- or overexpression-based approaches. Further optimization of transduction and screening protocols might enable such screens to assist physicians in the selection of optimal therapeutic strategies especially in poor risk AML. Disclosures: No relevant conflicts of interest to declare.

Ferroptosis Regulation by Nutrient Signaling

2021 ◽  
pp. 1-40
Author(s):  
Yingao Qi ◽  
Xiaoli Zhang ◽  
Zhihui Wu ◽  
Min Tian ◽  
Fang Chen ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Coenzyme Q ◽  
Monounsaturated Fatty Acids ◽  
Death Process ◽  
Regulated Cell Death ◽  
Pharmacological Targets ◽  
Tremendous Progress ◽  
Cell Death Process ◽  
Nutrient Signaling ◽  
Amp Activated Protein Kinase

Abstract Tremendous progress has been made in the field of ferroptosis since this regulated cell death process was first named in 2012. Ferroptosis is initiated upon redox imbalance and driven by excessive phospholipid peroxidation. Levels of multiple intracellular nutrients (iron, selenium, vitamin E, and coenzyme Q10) are intimately related to the cellular antioxidant system and participate in the regulation of ferroptosis. Dietary intake of monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) regulates ferroptosis by directly modifying the fatty acid composition in cell membranes. In addition, amino acids and glucose (energy stress) manipulate the ferroptosis pathway through the nutrient-sensitive kinases mechanistic target of rapamycin complex 1 (mTORC1) and AMP-activated protein kinase (AMPK). Understanding the molecular interaction between nutrient signals and ferroptosis sensors might help in the identification of the roles of ferroptosis in normal physiology and in the development of novel pharmacological targets for the treatment of ferroptosis-related diseases.

scholarly journals A genome-wide RNA interference screen reveals an essential CREB3L2-ATF5-MCL1 survival pathway in malignant glioma with therapeutic implications

2010 ◽  
Vol 16 (6) ◽  
pp. 671-677 ◽  
Author(s):  
Zhi Sheng ◽  
Li Li ◽  
Lihua J Zhu ◽  
Thomas W Smith ◽  
Andrea Demers ◽  
...  
Keyword(s):  
Rna Interference ◽  
Malignant Glioma ◽  
Therapeutic Implications ◽  
Genome Wide ◽  
Survival Pathway ◽  
A Genome

scholarly journals The Antifungal Protein AfpB Induces Regulated Cell Death in Its Parental Fungus Penicillium digitatum

mSphere ◽  
2020 ◽  
Vol 5 (4) ◽  
Author(s):  
Adrià Bugeda ◽  
Sandra Garrigues ◽  
Mónica Gandía ◽  
Paloma Manzanares ◽  
Jose F. Marcos ◽  
...  
Keyword(s):  
Cell Death ◽  
Food Safety ◽  
Human Health ◽  
Fungal Infections ◽  
Pathogenic Fungi ◽  
Penicillium Digitatum ◽  
Fungal Resistance ◽  
Death Process ◽  
Antifungal Proteins ◽  
Regulated Cell Death

ABSTRACT Filamentous fungi produce small cysteine-rich proteins with potent, specific antifungal activity, offering the potential to fight fungal infections that severely threaten human health and food safety and security. The genome of the citrus postharvest fungal pathogen Penicillium digitatum encodes one of these antifungal proteins, namely AfpB. Biotechnologically produced AfpB inhibited the growth of major pathogenic fungi at minimal concentrations, surprisingly including its parental fungus, and conferred protection to crop plants against fungal infections. This study reports an in-depth characterization of the AfpB mechanism of action, showing that it is a cell-penetrating protein that triggers a regulated cell death program in the target fungus. We prove the importance of AfpB interaction with the fungal cell wall to exert its killing activity, for which protein mannosylation is required. We also show that the potent activity of AfpB correlates with its rapid and efficient uptake by fungal cells through an energy-dependent process. Once internalized, AfpB induces a transcriptional reprogramming signaled by reactive oxygen species that ends in cell death. Our data show that AfpB activates a self-injury program, suggesting that this protein has a biological function in the parental fungus beyond defense against competitors, presumably more related to regulation of the fungal population. Our results demonstrate that this protein is a potent antifungal that acts through various targets to kill fungal cells through a regulated process, making AfpB a promising compound for the development of novel biofungicides with multiple fields of application in crop and postharvest protection, food preservation, and medical therapies. IMPORTANCE Disease-causing fungi pose a serious threat to human health and food safety and security. The limited number of licensed antifungals, together with the emergence of pathogenic fungi with multiple resistance to available antifungals, represents a serious challenge for medicine and agriculture. Therefore, there is an urgent need for new compounds with high fungal specificity and novel antifungal mechanisms. Antifungal proteins in general, and AfpB from Penicillium digitatum in particular, are promising molecules for the development of novel antifungals. This study on AfpB’s mode of action demonstrates its potent, specific fungicidal activity through the interaction with multiple targets, presumably reducing the risk of evolving fungal resistance, and through a regulated cell death process, uncovering this protein as an excellent candidate for a novel biofungicide. The in-depth knowledge on AfpB mechanistic function presented in this work is important to guide its possible future clinical and agricultural applications.

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