Snf1/AMPK fine-tunes TORC1 signaling in response to glucose starvation

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Feb. 7, 2023

The AMP-activated protein kinase (AMPK) and the target of rapamycin complex 1 (TORC1) are central modules two opposing signaling pathways that control eukaryotic cell growth metabolism in response to availability energy nutrients. Accordingly, depletion activates AMPK inhibit growth, while nutrients high levels activate TORC1 promote growth. Both mammals lower eukaryotes such as yeast, wired each other at different levels, which ensures homeostatic metabolism. In this context, a previous study (Hughes Hallett et al., 2015) reported is Snf1, prevents transient reactivation during early phase following acute glucose starvation, but underlying mechanism has remained elusive. Using combination unbiased mass spectrometry (MS)-based phosphoproteomics, genetic, biochemical, physiological experiments, we show here Snf1 temporally maintains inactive glucose-starved cells primarily through TORC1-regulatory Pib2. Our data, therefore, extend function Pib2 hub integrates both and, earlier, glutamine signals TORC1. We further demonstrate phosphorylates effector Sch9 within its N-terminal region thereby antagonizes phosphorylation C-terminal TORC1-target residue itself critical for activity. consequences Snf1-mediated physiologically additive sufficient explain role short-term inhibition acutely cells.

Language: Английский

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Cell surface protein aggregation triggers endocytosis to maintain plasma membrane proteostasis

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 28, 2023

The ability of cells to manage consequences exogenous proteotoxicity is key cellular homeostasis. While a plethora well-characterised machinery aids intracellular proteostasis, mechanisms involved in the response denaturation extracellular proteins remain elusive. Here we show that aggregation protein ectodomains triggers their endocytosis via macroendocytic route, and subsequent lysosomal degradation. Using ERBB2/HER2-specific antibodies reveal cross-linking specific fast receptor, independent clathrin dynamin. Upon aggregation, canonical clathrin-dependent cargoes are redirected into aggregation-dependent (ADE) pathway. ADE an actin-driven process, which morphologically resembles macropinocytosis. Physical chemical stress-induced surface also ADE, facilitating degradation lysosome. This study pinpoints domains as trigger for rapid uptake clearance besides its proteostatic function has potential implications pathological aggregates antibody-based therapies.

Language: Английский

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ARRDC5 expression is conserved in mammalian testes and required for normal sperm morphogenesis

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: April 17, 2023

Abstract In sexual reproduction, sperm contribute half the genomic material required for creation of offspring yet core molecular mechanisms essential their formation are undefined. Here, α-arrestin molecule arrestin-domain containing 5 (ARRDC5) is identified as an regulator mammalian spermatogenesis. Multispecies testicular tissue transcriptome profiling indicates that expression Arrdc5 testis enriched, if not specific, in mice, pigs, cattle, and humans. Knockout mice leads to male specific sterility due production low numbers immotile malformed. Spermiogenesis, final phase spermatogenesis when round spermatids transform spermatozoa, defective testes deficient mice. Also, epididymal knockouts unable capacitate fertilize oocytes. These findings establish ARRDC5 Considering role arrestin molecules modulators cellular signaling ubiquitination, a potential contraceptive target.

Language: Английский

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Reduced Dietary Protein Induces Changes in the Dental Proteome

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Abstract Experimental studies have demonstrated that nutritional changes during development can result in phenotypic to mammalian cheek teeth. This developmental plasticity of tooth morphology is an example plasticity. Because occurs through complex interactions between manifold processes, there are many potential mechanisms which contribute a tooth’s norm reaction. Determining the identity those and relative importance each them one main challenges understanding Quantitative proteomics combined with experimental allow for identification molecular contributors plastic response quantification expressed gene products. Here, we present results quantitative analysis mature upper first molars (M1s) Mus musculus from controlled feeding experiment. Pregnant nursing mothers were fed either low-dietary protein (10%) treatment diet or control (20%) diet. Expression tooth-related proteins, immune system actin-based myosin proteins significantly altered our sample. The recovery expression change was anticipated consistent previous proteomic studies. We also identified differential along systematic reduction expression, novel discoveries propose aim elucidate specific molar should prioritize investigations into relationships IGF regulation development. Research Highlights A low-protein major dental building within . Graphical

Language: Английский

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TEX38 localizes ZDHHC19 to the plasma membrane and regulates sperm head morphogenesis in mice

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(10)

Published: March 3, 2025

Sperm morphogenesis is a tightly regulated differentiation process, disruption of which leads to sperm malfunction and male infertility. Here, we show that Tex38 knockout (KO) mice are infertile. KO spermatids exhibit excess retention residual cytoplasm around the head, resulting in abnormal morphology with backward head bending. TEX38 interacts colocalizes ZDHHC19, testis-enriched acyltransferase catalyzing protein S-palmitoylation, at plasma membrane spermatids. ZDHHC19 each downregulated mouse testes lacking other protein. stabilizes localizes cultured cells vice versa, consolidating their interdependence. Mice deficient or harboring C142S mutation disables palmitoyltransferase activity display phenotypes resembling those mice. Strikingly, palmitoylates ARRDC5, an arrestin family regulating differentiation. Overall, our findings indicate forms stable complex spermatids, governs downstream S-palmitoylation proteins essential for morphological transformation

Language: Английский

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Phosphorylation of the Aly3 C-terminus impedes aberrant endocytosis of Schizosaccharomyces pombe hexose transporter Ght5

Journal of Cell Science, Journal Year: 2025, Volume and Issue: 138(7)

Published: April 1, 2025

ABSTRACT In the fission yeast Schizosaccharomyces pombe, transcriptional upregulation and cell-surface localization of hexose transporter Ght5 are required for cell proliferation in low glucose. As target rapamycin complex 2 (TORC2) signaling pathway inhibits α-arrestin Aly3-dependent endocytosis Ght5, we hypothesized that phosphorylation this endocytosis. To identify sites glucose, putatively phosphorylated serine/threonine residues Aly3 were replaced with alanine, showing C-terminal serine Aly3, but not necessary Expression could be at C-terminus led to increased ubiquitylation vacuolar accumulation reversion one alanine reversed those defects. Also, physically interacted HECT-type ubiquitin ligases Pub1 Pub3, these interactions surface This study reveals mechanisms by which is regulated so can adapt nutritional stress.

Language: Английский

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Chromosome segment scanning for gain- or loss-of-function screening (CHASING) and its application in metabolic engineering

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 2, 2024

Abstract Constructing a library of thousands single-gene knockout or interference strains is powerful tool to understand the relation between genotype and phenotype, but it labor cost intensive. Powered by computer-aided gene annotation functional grouping non-essential genes, we showed that targeting single directly specific observed phenotype could be quickly achieved for microorganism via constructing containing chromosome-segment-deletion per strain. As proof-of-concept, genome-scale consisting 70 B. subtilis was constructed CRISPR-based methods with six loss-of- gain-of-function phenotypes were screened out. To facilitate rapid genotyping, developed web visualize potential targets each chromosome segment associated particular function, successfully identifying genes valuable representative phenotypes. apply metabolic engineering, hosts improved production capacity acetoin lycopene in presence pathway genes. This work demonstrated significance our strategy ch romosome scanning g in- lo s s-of-function screen ing (CHASING) on genomics investigation, robust chassis chemical overproduction. Figure TOC

Language: Английский

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The Involvement of YNR069C in Protein Synthesis in the Baker’s Yeast, Saccharomyces cerevisiae

Biology, Journal Year: 2024, Volume and Issue: 13(3), P. 138 - 138

Published: Feb. 22, 2024

Maintaining translation fidelity is a critical step within the process of gene expression. It requires involvement numerous regulatory elements to ensure synthesis functional proteins. The efficient termination protein can play crucial role in preserving this fidelity. Here, we report on investigating unknown function, YNR069C (also known as BSC5), for its activity translation. We observed significant increase bypass premature stop codons upon deletion YNR069C. Interestingly, genomic arrangement ORF suggests compatible mode expression reliant translational readthrough, incorporating neighboring open reading frame. also showed that results an rate Based our results, propose may fidelity, impacting overall quantity and quality Our genetic interaction analysis supports hypothesis, associating regulation synthesis.

Language: Английский

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Divergent regulation of α-arrestin ARRDC3 function by ubiquitination

Molecular Biology of the Cell, Journal Year: 2023, Volume and Issue: 34(9)

Published: May 24, 2023

The α-arrestin ARRDC3 is a recently discovered tumor suppressor in invasive breast cancer that functions as multifaceted adaptor protein to control trafficking and cellular signaling. However, the molecular mechanisms function are unknown. Other arrestins known be regulated by posttranslational modifications, suggesting may subject similar regulatory mechanisms. Here we report ubiquitination key regulator of mediated primarily two proline-rich PPXY motifs C-tail domain. Ubiquitination essential for regulating GPCR Additionally, mediate degradation, dictate subcellular localization, required interaction with NEDD4-family E3 ubiquitin ligase WWP2. These studies demonstrate role reveal mechanism which divergent controlled.

Language: Английский

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Cell Surface Receptors

Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

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