Lysosomes’ fallback strategies: more than just survival or death

Frontiers in Cell and Developmental Biology, Год журнала: 2025, Номер 13

Опубликована: Март 11, 2025

Lysosomes are heterogeneous, acidic organelles whose proper functionality is critically dependent on maintaining the integrity of their membranes and acidity within lumen. When subjected to stress, lysosomal membrane can become permeabilized, posing a significant risk organelle’s survival necessitating prompt repair. Although numerous mechanisms for repair have been identified in recent years, progression lysosome-related diseases more closely linked alternative strategies when fail, particularly contexts aging pathogen infection. This review explores responses damage, including secretion contents interactions with lysosome-associated endolysosomal system. Furthermore, it examines role outside this system, such as endoplasmic reticulum (ER) Golgi apparatus, auxiliary These crucial understanding disease progression. For instance, spread misfolded proteins play key roles neurodegenerative advancement, while escape via lysosomotropic drug expulsion underlie cancer treatment resistance. Reexamining these fallback could provide new perspectives biology contribution

Язык: Английский

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Bro1 proteins determine tumor immune evasion and metastasis by controlling secretion or degradation of multivesicular bodies

Developmental Cell, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

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The cell biology of Extracellular Vesicles: A jigsaw puzzle with a myriad of pieces

Current Opinion in Cell Biology, Год журнала: 2025, Номер 94, С. 102519 - 102519

Опубликована: Апрель 22, 2025

Язык: Английский

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Coxiella burnetii manipulates the lysosomal protease cathepsin B to facilitate intracellular success

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Апрель 24, 2025

Abstract The obligate intracellular bacterium Coxiella burnetii establishes an replicative niche termed the -containing vacuole (CCV), which has been characterised as a bacterially modified phagolysosome. How C. withstands acidic and degradative properties of this compartment is not well understood. We demonstrate that key lysosomal protease cathepsin B actively selectively removed from burnetii- infected cells through mechanism involving Dot/Icm type IV-B secretion system effector CvpB. Overexpression leads to defects in CCV biogenesis bacterial replication, indicating removal protein represents strategy reduce hostility niche. In addition, we show infection mammalian induces wider cohort proteins, including B, extracellular milieu via dependent on retrograde traffic. This study reveals modulating hydrolase its promote success demonstrates incites secretory pathway maintain homoeostasis.

Язык: Английский

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Pathogenic variants in BORCS5 Cause a Spectrum of Neurodevelopmental and Neurodegenerative Disorders with Lysosomal Dysfunction

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Май 7, 2025

BORCS5 encodes a subunit of the BLOC-one-related complex (BORC), which is known to mediate kinesin-dependent anterograde movement lysosomes. Using whole-exome sequencing, we identified 12 cases from seven families carrying bi-allelic variants, including four loss-of-function and two missense variants. Carriers homozygous variants presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, neuropathological evidence diffuse neuroaxonal dystrophy. Individuals differently, microcephaly, developmental epileptic encephalopathy, intellectual disability, optic atrophy, spasticity, progressive disorders. In this group, MRI showed hypomyelination global cerebral consistent neurodegeneration. Borcs5 knockout in zebrafish exhibited motor deficits, seizures, mirroring patients' clinical presentation. At cellular level, but not resulted lower protein expression impaired BORC assembly, paralleled by perinuclear lysosomal clustering. However, both were associated reduced total proteolysis, activity hydrolases glucocerebrosidase cathepsin B, presence multilamellar bodies, indicating dysfunction. Our study reveals novel role for regulation function, addition its lysosomes, possibly underlying diverse manifestations individuals BORCS5-related

Язык: Английский

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Syntenin and CD63 Promote Exosome Biogenesis from the Plasma Membrane by Blocking Cargo Endocytosis

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

Опубликована: Май 27, 2023

Exosomes are small extracellular vesicles important in health and disease. Syntenin is thought to drive the biogenesis of CD63 exosomes by recruiting Alix ESCRT machinery endosomes, initiating an endosome-mediated pathway exosome biogenesis. Contrary this model, we show here that syntenin drives blocking endocytosis, thereby allowing accumulate at plasma membrane, primary site Consistent with these results, find inhibitors endocytosis induce exosomal secretion CD63, inhibits vesicular cargo proteins, high-level expression itself also endocytosis. These other results indicate bud primarily from their loading into exosomes, expression-dependent regulators biogenesis, even knockout cells.

Язык: Английский

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Monocytic Differentiation of Human Acute Myeloid Leukemia Cells: A Proteomic and Phosphoproteomic Comparison of FAB-M4/M5 Patients with and without Nucleophosmin 1 Mutations

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(10), С. 5080 - 5080

Опубликована: Май 7, 2024

Even though morphological signs of differentiation have a minimal impact on survival after intensive cytotoxic therapy for acute myeloid leukemia (AML), monocytic AML cell (i.e., classified as French/American/British (FAB) subtypes M4/M5) is associated with different responsiveness both to Bcl-2 inhibition (decreased responsiveness) and possibly also bromodomain (increased responsiveness). FAB-M4/M5 patients are heterogeneous regard genetic abnormalities, even common Nucleophosmin 1 (NPM1) insertions/mutations; further study the heterogeneity we did proteomic phosphoproteomic comparison (n = 13) without 12) NPM1 mutations. The profile NPM1-mutated was characterized by increased levels proteins involved in regulation endocytosis/vesicle trafficking/organellar communication. In contrast, cells mutations were several cytoplasmic translation, including large number ribosomal proteins. differences between two groups less extensive but reflected similar differences. To conclude, FAB classification/monocytic new targeted therapies (e.g., inhibition), our results shows that important biological characteristics leukemic cells.

Язык: Английский

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Organelle morphology and positioning orchestrate physiological and disease-associated processes

Current Opinion in Cell Biology, Год журнала: 2023, Номер 86, С. 102293 - 102293

Опубликована: Дек. 13, 2023

Язык: Английский

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Activation of the receptor KIT induces the secretion of exosome‐like small extracellular vesicles

Journal of Extracellular Biology, Год журнала: 2024, Номер 3(1)

Опубликована: Янв. 1, 2024

Abstract The receptor tyrosine kinase (RTK) KIT and its ligand stem cell factor (SCF) are essential for human mast (huMC) survival proliferation. HuMCs expressing oncogenic variants secrete large numbers of extracellular vesicles (EVs). role plays in regulating EV secretion has not been examined. Here, we investigated the effects stimulation or inhibition activity on small EVs (sEVs). In huMCs constitutively active KIT, quantity quality secreted sEVs positively correlated with status KIT. SCF‐mediated murine MCs, transiently expressed HeLa cells, enhanced release exosome markers. contrast, ligand‐mediated RTK EGFR cells did affect sEV secretion. induced by either ligand‐activated was remarkably decreased when were treated inhibitors, concomitant reduced markers sEVs. Similarly, signalling kinases like PI3K, MAPK significantly Thus, activation early cascades stimulate exosome‐like a regulated fashion, which may have implications KIT‐driven functions.

Язык: Английский

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Autophagic stress activates distinct compensatory secretory pathways in neurons

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

Опубликована: Ноя. 7, 2024

ABSTRACT Autophagic dysfunction is a hallmark of neurodegenerative disease, leaving neurons vulnerable to the accumulation damaged organelles and proteins. However, late onset diseases suggests that compensatory quality control mechanisms may be engaged delay deleterious effects induced by compromised autophagy. Neurons expressing common familial Parkinson’s disease (PD)-associated mutations in LRRK2 kinase exhibit defective Here, we demonstrate both primary murine human iPSC-derived harboring pathogenic upregulate secretion extracellular vesicles. We used unbiased proteomics characterize secretome G2019S found autophagic cargos including mitochondrial proteins were enriched. Based on these observations, hypothesized autophagosomes are rerouted toward when cell-autonomous degradation compromised, likely mediate clearance undegraded cellular waste. Immunoblotting confirmed release immunocytochemistry demonstrated secretory autophagy was upregulated neurons. also exosomes containing miRNAs. Live-cell imaging this upregulation exosomal dependent hyperactive activity, while pharmacological experiments indicate staves off apoptosis. Finally, show markers vesicle populations plasma from mice LRRK2. In sum, find secreted exosomes, waste disposal transcellular communication, respectively. propose increased contributes maintenance homeostasis, delaying progression over short term potentially contributing neuroinflammation longer term. SIGNIFICANCE A feature many dysfunction, resulting detrimental neuronal health. The diseases, however, alternative degeneration. Disease-causing mutation two populations. First, observe expulsion disposal. Second, facilitate communication. Thus, increases exosome homeostatic response undergoing chronic stress.

Язык: Английский

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