The integrated stress response in metabolic adaptation

Journal of Biological Chemistry, Год журнала: 2024, Номер 300(4), С. 107151 - 107151

Опубликована: Март 9, 2024

The Integrated Stress Response (ISR) refers to signaling pathways initiated by stress-activated eIF2‹ kinases. Distinct kinases respond different stress signals, including amino acid deprivation and mitochondrial stress. Such stress-induced phosphorylation attenuates general mRNA translation and, at the same time, stimulates preferential of specific downstream factors orchestrate an adaptive gene expression program. In recent years, there have been significant new advances in our understanding ISR during metabolic adaptation. Here, I discuss those advances, reviewing among others activation mechanisms response addition, review how regulates changes impact physiology pathology various disease models.

Язык: Английский

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Ribosome biogenesis and function in development and disease

Development, Год журнала: 2023, Номер 150(5)

Опубликована: Март 1, 2023

ABSTRACT Although differential transcription drives the development of multicellular organisms, ultimate readout a protein-coding gene is ribosome-dependent mRNA translation. Ribosomes were once thought as uniform molecular machines, but emerging evidence indicates that complexity and diversity ribosome biogenesis function should be given fresh look in context development. This Review begins with discussion different developmental disorders have been linked perturbations production function. We then highlight recent studies reveal how cells tissues exhibit variable levels protein synthesis, changes synthesis capacity can influence specific cell fate decisions. finish by touching upon heterogeneity stress responses These discussions importance considering both functional specialization disease.

Язык: Английский

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Cell competition: emerging signaling and unsolved questions

FEBS Letters, Год журнала: 2024, Номер 598(4), С. 379 - 389

Опубликована: Фев. 1, 2024

Multicellular communities have an intrinsic mechanism that optimizes their structure and function via cell–cell communication. One of the driving forces for such self‐organization multicellular system is cell competition, elimination viable unfit or deleterious cells interaction. Studies in Drosophila mammals identified multiple mechanisms competition caused by different types mutations cellular changes. Intriguingly, recent studies found “losers” commonly show reduced protein synthesis. In , reduction synthesis levels loser phosphorylation translation initiation factor eIF2α a bZip transcription Xrp1. Given variety stresses converge on thus global inhibition synthesis, may be machinery fitness removing stressed cells. this review, we summarize discuss emerging signaling critical unsolved questions, as well role competition.

Язык: Английский

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Trithorax regulates long-term memory in Drosophila through epigenetic maintenance of mushroom body metabolic state and translation capacity

PLoS Biology, Год журнала: 2025, Номер 23(1), С. e3003004 - e3003004

Опубликована: Янв. 27, 2025

The role of epigenetics and chromatin in the maintenance postmitotic neuronal cell identities is not well understood. Here, we show that histone methyltransferase Trithorax (Trx) required memory neurons Drosophila mushroom body (MB) to enable their capacity for long-term (LTM), but short-term (STM). Using MB-specific RNA-, ChIP-, ATAC-sequencing, find Trx maintains homeostatic expression several non-canonical MB-enriched transcripts, including orphan nuclear receptor Hr51, metabolic enzyme lactate dehydrogenase (Ldh). Through these key targets, facilitates a state characterized by high levels MBγ neurons. This supports protein translation, process essential LTM, STM. These data suggest Trx, classic regulator type specification during development, has additional functions maintaining underappreciated aspects neuron identity, such as state. Our work evidence suggesting energy metabolism an identity characteristic mediate LTM.

Язык: Английский

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Dynamic regulation of ribosome levels and translation during development

Seminars in Cell and Developmental Biology, Год журнала: 2022, Номер 136, С. 27 - 37

Опубликована: Июнь 18, 2022

Язык: Английский

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Collective cell migration relies on PPP1R15-mediated regulation of the endoplasmic reticulum stress response

Current Biology, Год журнала: 2024, Номер 34(7), С. 1390 - 1402.e4

Опубликована: Фев. 29, 2024

Язык: Английский

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A multi-omics genome-and-transcriptome single-cell atlas of human preimplantation embryogenesis reveals the cellular and molecular impact of chromosome instability

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Март 10, 2023

ABSTRACT The frequent acquisition of genomic abnormalities in human preimplantation embryos is a leading cause pregnancy loss, but does not necessarily prohibit healthy offspring. However, the impact on cellular states and development early embryo remains largely unclear. Here, we characterise aneuploidy reconstruct gene regulatory networks embryos, investigate expression developmental perturbations instigated by using single-cell genome-and-transcriptome sequencing (G&T-seq). At level, show that acquired numerical structural chromosomal aberrations are across all stages embryogenesis cell lineages. transcriptome identify regulators identity uncover network 248 transcription factors from 10 major modules distinct lineages embryos. By integrating DNA-with RNA-information, unveil how levels affected losses or gains corresponding genes embryonic cells development, as well copy-number aberrant factor perturb their cognate target euploid regions. Furthermore, reveal majority aneuploid delay reduced fitness, indicating competition within mosaic diploid-aneuploid embryo, which may contribute to selection against birth offspring In summary, our multi-modal analyses provide unprecedented insights into development.

Язык: Английский

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Xrp1 and Irbp18 trigger a feed-forward loop of proteotoxic stress to induce the loser status

PLoS Genetics, Год журнала: 2021, Номер 17(12), С. e1009946 - e1009946

Опубликована: Дек. 16, 2021

Cell competition induces the elimination of less-fit “loser” cells by fitter “winner” cells. In Drosophila , heterozygous mutant in ribosome genes, Rp/+ known as Minutes are outcompeted wild-type display proteotoxic stress and oxidative response, which drive loser status. Minute cell also requires transcription factors Irbp18 Xrp1, but how these contribute to status is partially understood. Here we provide evidence that initial RpS3/+ Xrp1-independent. However, Xrp1 sufficient induce otherwise necessary for high levels found Surprisingly, induced downstream stress, required competitive suffering from or overexpressing Nrf2. Our data suggests a feed-forward loop between Nrf2 drives become losers.

Язык: Английский

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Cell competition is driven by Xrp1-mediated phosphorylation of eukaryotic initiation factor 2α

PLoS Genetics, Год журнала: 2021, Номер 17(12), С. e1009958 - e1009958

Опубликована: Дек. 6, 2021

Cell competition is a context-dependent cell elimination via cell-cell interaction whereby unfit cells (‘losers’) are eliminated from the tissue when confronted with fitter (‘winners’). Despite extensive studies, mechanism that drives loser’s death and its physiological triggers remained elusive. Here, through genetic screen in Drosophila , we find endoplasmic reticulum (ER) stress causes competition. Mechanistically, ER upregulates bZIP transcription factor Xrp1, which promotes phosphorylation of eukaryotic translation initiation eIF2α kinase PERK, leading to elimination. Surprisingly, our data show different such as ribosomal protein mutations or RNA helicase Hel25E converge on upregulation leads thus reduction global synthesis apoptosis wild-type cells. These findings not only uncover core pathway but also open way understanding

Язык: Английский

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Ribosomal protein mutations and cell competition: autonomous and nonautonomous effects on a stress response

Genetics, Год журнала: 2023, Номер 224(3)

Опубликована: Июнь 2, 2023

Abstract Ribosomal proteins (Rps) are essential for viability. Genetic mutations affecting Rp genes were first discovered in Drosophila, where they represent a major class of haploinsufficient mutations. One mutant copy gives rise to the dominant “Minute” phenotype, characterized by slow growth and small, thin bristles. Wild-type (WT) Minute cells compete mosaics, that is, Rp+/− preferentially lost when their neighbors wild-type genotype. Many features gene haploinsufficiency (i.e. phenotypes) mediated transcriptional program. In reduced translation under control Xrp1, bZip-domain transcription factor induced leads ultimately phosphorylation eIF2α consequently inhibition most translation. phenotypes also transcriptionally yeast mammals. mammals, Impaired Ribosome Biogenesis Checkpoint activates p53. Recent findings link other cellular stresses, including DNA damage response endoplasmic reticulum stress. We suggest cell competition results from nonautonomous inputs stress responses, bringing decisions between adaptive apoptotic outcomes influence nearby cells. eliminates aneuploid which loss chromosome haploinsufficiency. The effects on whole organism, flies or humans with Diamond-Blackfan Anemia, may be inevitable consequences pathways useful eliminating individual mosaics. Alternatively, apparently deleterious organism might adaptive, preventing even more detrimental outcomes. example, p53 activation appears suppress oncogenic

Язык: Английский

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