Maintaining Iron Homeostasis Is the Key Role of Lysosomal Acidity for Cell Proliferation

Weber, Ross A.; Yen, Frederick S.; Nicholson, Shirony P.V.; Alwaseem, Hanan; Bayraktar, Erol C.; Alam, Mohammad Atif; Timson, Rebecca C.; La, Konnor; Abu-Remaileh, Monther; Molina, Henrik; Birsoy, Kıvanç

doi:10.1016/j.molcel.2020.01.003

Cited by 164 publications

(146 citation statements)

References 46 publications

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“…2f). We found that knockdown of many lysosome/autophagy-related genes affected both lysosomal status and iron levels, reflecting the key role of lysosomes in iron homeostasis 52,53 . Among these genes, we found WDR45, which is involved in autophagosome formation and lysosomal degradation and is also associated with Neurodegeneration with Brain Iron Accumulation (NBIA) in line with previous studies 54,55 .…”

Section: Genome-wide Crispri/a Screens Elucidate Pathways Controllingmentioning

confidence: 87%

Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis

Tian

Abarientos

Hong

et al. 2020

Preprint

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SUMMARYSingle-cell transcriptomics provide a systematic map of gene expression in different human cell types. The next challenge is to systematically understand cell-type specific gene function. The integration of CRISPR-based functional genomics and stem cell technology enables the scalable interrogation of gene function in differentiated human cells. Here, we present the first genome-wide CRISPR interference and CRISPR activation screens in human neurons.We uncover pathways controlling neuronal response to chronic oxidative stress, which is implicated in neurodegenerative diseases. Unexpectedly, knockdown of the lysosomal protein prosaposin strongly sensitizes neurons, but not other cell types, to oxidative stress by triggering the formation of lipofuscin, a hallmark of aging, which traps iron, generating reactive oxygen species and triggering ferroptosis. We also determine transcriptomic changes in neurons following perturbation of genes linked to neurodegenerative diseases. To enable the systematic comparison of gene function across different human cell types, we establish a data commons named CRISPRbrain.

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Section: Genome-wide Crispri/a Screens Elucidate Pathways Controllingmentioning

confidence: 87%

Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis

Tian

Abarientos

Hong

et al. 2020

Preprint

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“…The increase in proteome allocation to vacuole, under nitrogen limitation, was accompanied by the increase in TFs (Met4 and Met32) that regulate sulfur amino acid pathways (e.g., cysteine, methionine) and is consistent with previous results, under nitrogen limitation, where transcriptional upregulation of methionine and sulfur amino acid pathways was reported ( Figure 3G, S3) (Kresnowati et al, 2006). The increase in proteome allocation to vacuole, along with the GO term Fe-S binding discussed above ( Figure 3E), was interesting as iron and amino acid homeostasis together with vacuole are considered important for the maintenance of mitochondrial functions that is crucial for the cellular energy budget in yeast (Hughes et al, 2020;Shen, 2020;Weber et al, 2020). In addition, as many vacuolar processes are evolutionary conserved and implicated in diseases such as cancer, diabetes and neurodegeneration further investigation under these conditions could be pertinent for identifying underlying molecular mechanisms in S. cerevisiae (Lawrence and Zoncu, 2019;Reggiori and Klionsky, 2013).…”

Section: Distinct Translation Constrains Control Diversity In Carbonmentioning

confidence: 53%

Proteome overabundance enables respiration but limitation onsets carbon overflow

Kumar¹,

Lahtvee²

2020

Preprint

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Central carbon metabolism produces energy and precursor metabolites for biomass in heterotrophs. Carbon overflow yields metabolic byproducts and, here, we examined its dependency on nutrient and growth using the unicellular eukaryotic model organism Saccharomyces cerevisiae. We performed quantitative proteomics analysis together with metabolic modeling and found that proteome overabundance enabled respiration, and variation in energy efficiency caused distinct composition of biomass at different carbon to nitrogen ratio and growth rate. Our results showed that ceullar resource allocation for ribosomes was determinative of growth rate, but energy constrains on protein synthesis incepted carbon overflow by prioritizing abundance of ribosomes and glycolysis over mitochondria. We proved that glycolytic efficiency affected energy metabolism by making a trade-off between low and high energy production pathways. Finally, we summarized cellular energy budget underlying nutrient-responsive and growth rate-dependent carbon overflow, and suggested implications of results for bioprocesses and pathways relevant in cancer metabolism in humans.

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“…Both nutritional iron deficiency and genetic defects affecting cellular iron uptake cause immunodeficiency in humans. The role of iron in the immune system has been particularly strongly linked to lymphocyte proliferation in response to antigen (Kurz et al 2011;Yambire et al 2019;Weber et al 2020;Cronin et al 2019). Our data provide a novel insight into the unique regulation of iron uptake in proliferating GC B cells.…”

Section: Discussionmentioning

confidence: 78%

Endophilin A2 regulates B cell protein trafficking and humoral responses

Malinova

Wasim

Engels

et al. 2020

Preprint

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HIGHLIGHTS• Genome-wide CRISPR screens comprehensively identify genes regulating antigen uptake in B cells • B cell receptor-mediated antigen internalization is mediated by both epsin1-dependent clathrincoated pits and a novel fast endophilin A2-mediated endocytosis.• Endophilin A2 is required for peripheral B cell development, antigen-specific germinal center responses and high-affinity IgG production.• Endophilin A2 is broadly essential for B cell intracellular trafficking pathways providing metabolic support of germinal center B cell proliferation, in part through regulation of iron uptake. SUMMARYAntigen-specific B cell responses require endosomal trafficking to regulate antigen uptake and presentation to helper T cells, and to control expression and signaling of immune receptors. However, the molecular composition of B cell endosomal trafficking pathways and their specific roles in B cell responses have not been systematically investigated. Here we report high-throughput identification of genes regulating B cell receptor (BCR)-mediated antigen internalization using genome-wide functional screens. We show that antigen internalization depends both on clathrin-coated pits and on clathrinindependent endocytosis mediated by endophilin A2. Although endophilin A2 is dispensable for presentation of the endocytosed antigen, it is required for metabolic support of germinal center (GC) B cell proliferation, in part through regulation of iron uptake. Consequently, endophilin A2 deficient mice show selective defects in GC B cell responses and production of high-affinity IgG. The requirement for endophilin A2 highlights a unique importance of clathrin-independent intracellular trafficking in GC B cell clonal expansion and antibody responses.Endoplasmic reticulum

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Maintaining Iron Homeostasis Is the Key Role of Lysosomal Acidity for Cell Proliferation

Cited by 164 publications

References 46 publications

Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis

Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis

Proteome overabundance enables respiration but limitation onsets carbon overflow

Endophilin A2 regulates B cell protein trafficking and humoral responses

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