Chronic stress antagonizes formation of Stress Granules DOI Open Access
Yuichiro Adachi, Allison M. Williams, Masashi Masuda

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 3, 2024

Abstract Chronic stress mediates cellular changes that can contribute to human disease. However, fluctuations in RNA metabolism caused by chronic have been largely neglected the field. Stress granules (SGs) are cytoplasmic ribonucleoprotein condensates formed response stress-induced inhibition of mRNA translation and polysome disassembly. Despite broad interest SG assembly disassembly acute stress, has not extensively investigated. In this study, we show cells pre-conditioned with low dose (24-hour exposure) stresses such as oxidative endoplasmic reticulum mitochondrial starvation, fail assemble SGs stress. While is drastically decreased cells, profiling analysis reveals partial preservation polysomes resistant puromycin-induced We showed slows down rate at elongation phase triggers phosphorylation factor eEF2. Polysome followed RNase treatment confirmed induces ribosome stalling. stalling distinct from collisions known trigger a specific pathway. summary, stalling, which blocks formation subsequent Significant statements dynamic biocondensates assembled proposed survival exposed toxic conditions. Although mechanisms well understood, role modulating unclear. Here, despite translation. Mechanistically, prevents formation. This finding suggests chronically stressed or diseased may dysfunctional could inhibit cell promote

Язык: Английский

Transcriptome-wide mRNA condensation precedes stress granule formation and excludes stress-induced transcripts DOI Creative Commons
Hendrik Glauninger, Jared A.M. Bard, Caitlin J. Wong Hickernell

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 16, 2024

Abstract Stress-induced condensation of mRNA and proteins into stress granules is conserved across eukaryotes, yet the function, formation mechanisms, relation to well-studied transcriptional responses remain largely unresolved. exposure ribosome-free following translational shutoff thought cause by allowing new multivalent RNA-dependent interactions, with RNA length associated interaction capacity driving increased condensation. Here we show that, in striking contrast, virtually all species condense response multiple unrelated stresses budding yeast, plays a minor role, instead, stress-induced transcripts are preferentially excluded from condensates, enabling their selective translation. Using both endogenous genes reporter constructs, that translation initiation blockade, rather than resulting RNA, causes These initiation-inhibited condensates (TIICs) biochemically detectable even when granules, defined as microscopically visible foci, absent or blocked. TIICs occur unstressed yeast cells, and, during stress, grow before appearance granules. primarily due timing expression, sequence features. Together, our results reveal simple system which cells redirect activity newly synthesized broad implications for cellular regulation changing conditions.

Язык: Английский

Процитировано

11
DDX3X and Stress Granules: Emerging Players in Cancer and Drug Resistance DOI Open Access
Han Zhang,

Paula M. Mañán-Mejías,

Hannah N. Miles

и другие.

Cancers, Год журнала: 2024, Номер 16(6), С. 1131 - 1131

Опубликована: Март 12, 2024

The DEAD (Asp-Glu-Ala-Asp)-box helicase 3 X-linked (DDX3X) protein participates in many aspects of mRNA metabolism and stress granule (SG) formation. DDX3X has also been associated with signal transduction cell cycle regulation that are important maintaining cellular homeostasis. Malfunctions have implicated multiple cancers, including brain cancer, leukemia, prostate head neck cancer. Recently, literature reported SG-associated cancer drug resistance, which correlates a negative disease prognosis. Based on the connections between DDX3X, SG formation, pathology, targeting may be promising direction for therapeutics development. In this review, we describe biological functions terms metabolism, transduction, regulation. Furthermore, summarize contributions formation adaptation. Finally, discuss relationships SG, current research progress several inhibitors treatment.

Язык: Английский

Процитировано

9
Calcium signaling from damaged lysosomes induces cytoprotective stress granules DOI Creative Commons

Jacob Duran,

Jaime Salinas-Chavira,

Rui Ping Wheaton

и другие.

The EMBO Journal, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 12, 2024

Abstract Lysosomal damage induces stress granule (SG) formation. However, the importance of SGs in determining cell fate and precise mechanisms that mediate SG formation response to lysosomal remain unclear. Here, we describe a novel calcium-dependent pathway controlling formation, which promotes survival during damage. Mechanistically, calcium-activated protein ALIX transduces signals by eIF2α phosphorylation after sensing calcium leakage. enhances promoting association between PKR its activator PACT, with galectin-3 inhibiting this interaction; these regulatory events occur on damaged lysosomes. We further find plays crucial role upon caused factors such as SARS-CoV-2 ORF3a , adenovirus, malarial pigment, proteopathic tau, or environmental hazards. Collectively, data provide insights into mechanism implicate it diseases associated lysosomes SGs.

Язык: Английский

Процитировано

7
A mechanism that transduces lysosomal damage signals to stress granule formation for cell survival DOI Creative Commons

Jacob Duran,

Suttinee Poolsup, Lee Allers

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Март 30, 2024

SUMMARY Lysosomal damage poses a significant threat to cell survival. Our previous work has reported that lysosomal induces stress granule (SG) formation. However, the importance of SG formation in determining fate and precise mechanisms through which triggers remains unclear. Here, we show is initiated via novel calcium-dependent pathway plays protective role promoting survival response damage. Mechanistically, demonstrate during damage, ALIX, calcium-activated protein, transduces signals by sensing calcium leakage induce controlling phosphorylation eIF2α. ALIX modulates eIF2α regulating association between PKR its activator PACT, with galectin-3 exerting negative effect on this process. We also found regulatory event occur damaged lysosomes. Collectively, these investigations reveal insights into regulation triggered shed light interaction lysosomes SGs. Importantly, for physiological context inflicted SARS-CoV-2 ORF3a, adenovirus infection, Malaria hemozoin, proteopathic tau as well environmental hazard silica.

Язык: Английский

Процитировано

3
Novel Efficient Lipid-Based Delivery Systems Enable a Delayed Uptake and Sustained Expression of mRNA in Human Cells and Mouse Tissues DOI Creative Commons

Artem G. Fedorovskiy,

Denis N. Antropov,

Anton S. Dome

и другие.

Pharmaceutics, Год журнала: 2024, Номер 16(5), С. 684 - 684

Опубликована: Май 19, 2024

Over the past decade, mRNA-based therapy has displayed significant promise in a wide range of clinical applications. The most striking example leap development mRNA technologies was mass vaccination against COVID-19 during pandemic. emergence large-scale technology and positive experience immunization sparked antiviral anti-cancer vaccines as well therapeutic agents for genetic other diseases. To facilitate delivery, lipid nanoparticles (LNPs) have been successfully employed. However, diverse use approaches requires adaptable LNP delivery systems that can control kinetics uptake expression target cells. Here, we report effective into cultured mammalian cells (HEK293T, HeLa, DC2.4) living mouse muscle tissues by liposomes containing either 1,26-bis(cholest-5-en-3β-yloxycarbonylamino)-7,11,16,20-tetraazahexacosane tetrahydrochloride (2X3) or newly applied 1,30-bis(cholest-5-en-3β-yloxycarbonylamino)-9,13,18,22-tetraaza-3,6,25,28-tetraoxatriacontane (2X7) cationic lipids. Using end-point real-time monitoring Fluc expression, showed these LNPs exhibited an unusually delayed (of over 10 h case 2X7-based system) but had highly efficient prolonged reporter activity Accordingly, both formulations decorated with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG2000) provided luciferase production mice, peaking on day 3 after intramuscular injection. Notably, bioluminescence observed only at site injection caudal thigh muscles, thereby demonstrating local model gene interest. developed hold prophylactic applications, where sustained synthesis defensive proteins is required, open doors to new possibilities therapies.

Язык: Английский

Процитировано

1
Translation Landscape of Stress Granules DOI Creative Commons
Qiang Guo,

Yichun Wu,

Xing Wang

и другие.

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Июнь 12, 2024

Abstract Stress granules, cytoplasmic assemblies of RNA-binding proteins and mRNAs formed during cellular stress, are implicated in translational control. However, their exact functions remain elusive. Here, we employed cryogenic correlative light electron microscopy to visualize stress granules native environment reconstructed them 3D using tomography. This approach provided the first quantitative spatial analysis machinery within granules. Our findings suggest that have a limited impact on global translation regulation but serve protect small ribosomal subunits pre-initiation complexes (PICs) from degradation. Numerical simulations based phase-field model accurately reproduced distribution components inside outside shedding thermodynamic principles governing this process.

Язык: Английский

Процитировано

1
The G3BP Stress-Granule Proteins Reinforce the Translation Program of the Integrated Stress Response DOI Creative Commons
Jarrett Smith, David P. Bartel

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 5, 2024

ABSTRACT When mammalian cells are exposed to extracellular stress, they coordinate the condensation of stress granules (SGs) through action key nucleating proteins G3BP1 and G3BP2 (G3BPs) and, simultaneously, undergo a massive reduction in translation. 1–5 Although SGs G3BPs have been linked this translation response, their overall impact has unclear. Here, we investigate longstanding question how, indeed whether, shape response. We find that enriched for mRNAs resistant stress-induced shutdown. accurate recruitment these stress-resistant does require context combination optogenetic tools spike-normalized ribosome profiling demonstrates necessary sufficient both help prioritize suppress cytosolic Together results support model which reinforce program by prioritizing resident mRNAs.

Язык: Английский

Процитировано

1
Chronic stress antagonizes formation of Stress Granules DOI Open Access
Yuichiro Adachi, Allison M. Williams, Masashi Masuda

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 3, 2024

Abstract Chronic stress mediates cellular changes that can contribute to human disease. However, fluctuations in RNA metabolism caused by chronic have been largely neglected the field. Stress granules (SGs) are cytoplasmic ribonucleoprotein condensates formed response stress-induced inhibition of mRNA translation and polysome disassembly. Despite broad interest SG assembly disassembly acute stress, has not extensively investigated. In this study, we show cells pre-conditioned with low dose (24-hour exposure) stresses such as oxidative endoplasmic reticulum mitochondrial starvation, fail assemble SGs stress. While is drastically decreased cells, profiling analysis reveals partial preservation polysomes resistant puromycin-induced We showed slows down rate at elongation phase triggers phosphorylation factor eEF2. Polysome followed RNase treatment confirmed induces ribosome stalling. stalling distinct from collisions known trigger a specific pathway. summary, stalling, which blocks formation subsequent Significant statements dynamic biocondensates assembled proposed survival exposed toxic conditions. Although mechanisms well understood, role modulating unclear. Here, despite translation. Mechanistically, prevents formation. This finding suggests chronically stressed or diseased may dysfunctional could inhibit cell promote

Язык: Английский

Процитировано

0