Exosome biogenesis: machinery, regulation, and therapeutic implications in cancer

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: Nov. 1, 2022

Abstract Exosomes are well-known key mediators of intercellular communication and contribute to various physiological pathological processes. Their biogenesis involves four steps, including cargo sorting, MVB formation maturation, transport MVBs, fusion with the plasma membrane. Each process is modulated through competition or coordination multiple mechanisms, whereby diverse repertoires molecular cargos sorted into distinct subpopulations exosomes, resulting in high heterogeneity exosomes. Intriguingly, cancer cells exploit strategies, such as aberrant gene expression, posttranslational modifications, altered signaling pathways, regulate biogenesis, composition, eventually functions exosomes promote progression. Therefore, exosome biogenesis-targeted therapy being actively explored. In this review, we systematically summarize recent progress understanding machinery how it regulated context cancer. particular, highlight pharmacological targeting a promising therapeutic strategy.

Language: Английский

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Phosphoinositides as membrane organizers

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 23(12), P. 797 - 816

Published: May 19, 2022

Language: Английский

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Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired

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

Published: Aug. 18, 2023

Abstract Mitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible generating most of the energy needed to sustain contraction. Dysfunctional mitochondria normally degraded via intracellular degradation pathways that converge on lysosome. Here, we identified an alternative mechanism eliminate when lysosomal function compromised. We show inhibition leads increased secretion in large extracellular vesicles (EVs). The EVs produced multivesicular bodies, and their release independent autophagy. Deletion small GTPase Rab7 cells or adult mouse heart containing ubiquitinated cargos, including intact mitochondria. secreted captured by macrophages without activating inflammation. Hearts from aged mice Danon disease patients have levels indicating activation vesicular during pathophysiology. Overall, findings establish eliminated through endosomal pathway inhibited.

Language: Английский

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Mitochondrial-derived vesicles in metabolism, disease, and aging

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(1), P. 21 - 35

Published: Jan. 1, 2024

Mitochondria are central hubs of cellular metabolism and tightly connected to signaling pathways. The dynamic plasticity mitochondria fuse, divide, contact other organelles flux metabolites is their function. To ensure bona fide functionality interconnectivity, diverse molecular mechanisms evolved. An ancient long-overlooked mechanism the generation mitochondrial-derived vesicles (MDVs) that shuttle selected mitochondrial cargoes target organelles. Just recently, we gained significant insight into functions MDV transport, ranging from role in quality control immune signaling, thus demonstrating unexpected physiological aspects transport. This review highlights origin MDVs, biogenesis, cargo selection, with a specific focus on contribution transport across cell organ barriers. Additionally, implications MDVs peroxisome neurodegeneration, metabolism, aging, cancer discussed.

Language: Английский

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Disrupted degradative sorting of TLR7 is associated with human lupus

Science Immunology, Journal Year: 2024, Volume and Issue: 9(92)

Published: Jan. 11, 2024

Hyperactive TLR7 signaling has long been appreciated as driver of autoimmune disease in mouse models. Recently, gain-of-function mutations were identified a monogenic cause human lupus. is an intracellular transmembrane receptor, sensing RNA breakdown products within late endosomes. Here, we show that endosome dysfunction leads to unrestricted and associated with The endosomal BORC complex together the small GTPase Arl8b controls levels by regulating receptor turnover. This requires direct interaction between TLR7-associated trafficking factor Unc93b1 Arl8b. We UNC93B1 mutation patient childhood-onset lupus, which results reduced accumulation. Therefore, failure control turnover sufficient break immunological tolerance nucleic acids. Our highlight importance intact endomembrane system preventing pathological disease.

Language: Английский

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SARS-CoV-2 virulence factor ORF3a blocks lysosome function by modulating TBC1D5-dependent Rab7 GTPase cycle

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 6, 2024

Abstract SARS-CoV-2, the causative agent of COVID-19, uses host endolysosomal system for entry, replication, and egress. Previous studies have shown that SARS-CoV-2 virulence factor ORF3a interacts with lysosomal tethering HOPS complex blocks HOPS-mediated late endosome autophagosome fusion lysosomes. Here, we report infection leads to hyperactivation endosomal small GTP-binding protein Rab7, which is dependent on expression. We also observed Rab7 in naturally occurring variants encoded by distinct variants. found ORF3a, Vps39, sequesters GAP TBC1D5 displaces from this complex. Thus, disrupts GTP hydrolysis cycle beneficial viral production, whereas GDP-locked mutant strongly reduces replication. Hyperactivation ORF3a-expressing cells impaired CI-M6PR retrieval endosomes trans-Golgi network, disrupting biosynthetic transport newly synthesized hydrolases Furthermore, Rab7- Arl8b-positive compartments was strikingly reduced upon As egress requires Arl8b, these findings suggest ORF3a-mediated serves a multitude functions, including blocking endolysosome formation, interrupting hydrolases, promoting

Language: Английский

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Noncanonical roles of ATG5 and membrane atg8ylation in retromer assembly and function

eLife, Journal Year: 2025, Volume and Issue: 13

Published: Jan. 7, 2025

ATG5 is one of the core autophagy proteins with additional functions such as noncanonical membrane atg8ylation, which among a growing number biological outputs includes control tuberculosis in animal models. Here, we show that associates retromer’s components VPS26, VPS29, and VPS35 modulates retromer function. Knockout blocked trafficking key glucose transporter sorted by retromer, GLUT1, to plasma membrane. Knockouts other genes essential for component, affected GLUT1 sorting, indicating atg8ylation process affects function endosomal sorting. The contribution sorting was independent canonical autophagy. These findings expand scope specific processes cell dependent on its known interactors.

Language: Английский

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Coordination between ESCRT function and Rab conversion during endosome maturation

The EMBO Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 5, 2025

Language: Английский

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Disrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson’s disease

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

Published: April 19, 2023

Abstract Accumulation of α-synuclein into toxic oligomers or fibrils is implicated in dopaminergic neurodegeneration Parkinson’s disease. Here we performed a high-throughput, proteome-wide peptide screen to identify protein-protein interaction inhibitors that reduce oligomer levels and their associated cytotoxicity. We find the most potent inhibitor disrupts direct between C-terminal region CHarged Multivesicular body Protein 2B (CHMP2B), component Endosomal Sorting Complex Required for Transport-III (ESCRT-III). show impedes endolysosomal activity via this interaction, thereby inhibiting its own degradation. Conversely, restores function decreases multiple models, including female male human cells harboring disease-causing mutations. Furthermore, protects neurons from α-synuclein-mediated degeneration hermaphroditic C. elegans preclinical disease models using rats. Thus, α-synuclein-CHMP2B potential therapeutic target neurodegenerative disorders.

Language: Английский

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The membrane surface as a platform that organizes cellular and biochemical processes

Developmental Cell, Journal Year: 2023, Volume and Issue: 58(15), P. 1315 - 1332

Published: July 6, 2023

Membranes are essential for life. They act as semi-permeable boundaries that define cells and organelles. In addition, their surfaces actively participate in biochemical reaction networks, where they confine proteins, align partners, directly control enzymatic activities. Membrane-localized reactions shape cellular membranes, the identity of organelles, compartmentalize processes, can even be source signaling gradients originate at plasma membrane reach into cytoplasm nucleus. The surface is, therefore, an platform upon which myriad processes scaffolded. this review, we summarize our current understanding biophysics biochemistry membrane-localized with particular focus on insights derived from reconstituted systems. We discuss how interplay factors results self-organization, condensation, assembly, activity, emergent properties them.

Language: Английский

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