CHIP protects lysosomes from CLN4 mutant-induced membrane damage
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ABSTRACT:
PROVIDER: PRJNA1288481 | ENA |
REPOSITORIES: ENA
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Project description:Understanding how cells mitigate lysosomal damage is critical for unraveling pathogenic mechanisms of lysosome-related diseases. Here we generated and characterized iPSC-derived neurons (i3Neuron) bearing Ceroid Lipofuscinosis Neuronal 4 (CLN4)-linked DNAJC5 mutations, which revealed extensive lysosomal abnormality in mutant neurons. In vitro membrane-damaging experiments establish lysosome damages, caused by lysosome-associated CLN4 mutant aggregates, as a critical pathogenic linchpin in CLN4-associated neurodegeneration. Intriguingly, in non-neuronal cells, a ubiquitin-dependent microautophagy mechanism downregulates CLN4 aggregates to counteract CLN4-associated lysotoxicity. Genome-wide CRISPR screens identify the ubiquitin ligase CHIP as a central microautophagy regulator that confers ubiquitin-dependent lysosome protection. Importantly, CHIP’s lysosome protection function is transferrable: ectopic CHIP improves lysosomal function in CLN4 i3Neurons and effectively alleviates lipofuscin accumulation and cell death in a Drosophila CLN4 disease model. Our study establishes CHIP-mediated microautophagy as a key organelle guardian that preserves lysosome integrity, offering new insights into therapeutic development for lysosome-related neurodegenerative diseases.
2025-07-15 | GSE302082 | GEO
Project description: Not available
| S-EPMC11870535 | biostudies-literature
Project description:Understanding how cells mitigate lysosomal damage is critical for unraveling pathogenic mechanisms of lysosome related diseases. Here we use organelle-specific proteomics in iPSC derived neurons (i3Neuron) and an in vitro lysosome damaging assay to demonstrate that lysosome damage, caused by the aggregation of Ceroid Lipofuscinosis Neuronal 4 (CLN4) linked DNAJC5 mutants on lysosomal membranes, serves as a critical pathogenic linchpin in CLN4 associated neurodegeneration. Intriguingly, in non neuronal cells, a ubiquitin dependent microautophagy mechanism downregulates CLN4 aggregates to counteract CLN4 associated lysotoxicity. Genome wide CRISPR screens identify the ubiquitin ligase CHIP as a central microautophagy regulator that confers ubiquitin dependent lysosome protection. Importantly, CHIP lysosome protection function is transferrable, as ectopic CHIP improves lysosomal function in CLN4 i3Neurons, and effectively alleviates lipofuscin accumulation and neurodegeneration in a Drosophila CLN4 disease model. Our study establishes CHIP mediated microautophagy as a key organelle damage guardian that preserves lysosome integrity, offering new insights into therapeutic development for CLN4 and other lysosome related neurodegenerative diseases.
2024-12-11 | MSV000096646 | MassIVE
Project description:Lysosomal membrane integrity is essential for cell survival, but how damage sensing is spatiotemporally coupled to repair remains poorly understood. Recruitment and assembly of Endosomal Sorting Complex Required for Transport (ESCRT) I-III rapidly counteracts membrane damage, but how ESCRT-I recognizes defective lysosomal membranes is unclear. Leveraging genome-wide CRISPRi screens in a damage-sensitized genetic background, we discovered LC3/GABARAP Assisted Stimulator for ESCRT Recruitment (LASER), a multicomponent protein assembly that forms rapidly upon calcium release from damaged lysosomes, and which couples sensing of lysosomal membrane damage to ESCRT-dependent repair. At the core of LASER is Trk-fused gene (TFG), an ER exit sites (ERES) resident protein that translocates to damaged lysosomes by binding to ATG8 family proteins (LC3/GABARAP) conjugated to lysosomal phospholipids. ATG8-bound TFG forms oligomeric assemblies that directly recruit the essential ESCRT-I subunit, Tumor Suppressor Gene 101 (TSG101), via conserved motif recognition enhanced by avidity-driven interactions. TFG binding to TSG101 stimulates sequential ESCRT I-II-III polymerization and promotes membrane repair. TFG mutations that drive hereditary spastic paraplegia disrupt its oligomerization and impair lysosomal ESCRT recruitment and membrane resealing, implicating defective repair as a driver of TFG-associated neurodegeneration. Thus, LASER promotes ESCRT polymerization at damaged lysosomes and couples damage sensing to membrane repair.
2026-04-20 | GSE328484 | GEO
Project description:We report that lysosomal damage is a hitherto unknown inducer of stress granule (SG) formation and that the process termed membrane atg8ylation coordinates SG formation with mTOR inactivation during lysosomal stress. SGs were induced by lysosome-damaging agents including SARS-CoV-2ORF3a, Mycobacterium tuberculosis, and proteopathic tau. During damage, mammalian ATG8s directly interacted with the core SG proteins NUFIP2 and G3BP1. Atg8ylation was needed for their recruitment to damaged lysosomes independently of SG condensates whereupon NUFIP2 contributed to mTOR inactivation via the Ragulator-RagA/B complex. Thus, cells employ membrane atg8ylation to control and coordinate SG and mTOR responses to lysosomal damage.
2022-06-09 | MSV000089622 | MassIVE
Project description:<p>Perturbations in lysosome integrity are tightly linked to neurological disorders and ageing, but the underlying pathogenic mechanisms are incompletely understood. Using an unbiased proteomic approach, we here identified the bridge-like lipid transport protein VPS13C/PARK23 as a key component of a global early response pathway to lysosome damage. VPS13C readily binds lysosomes under mechanical or osmotic tension in anticipation of membrane lesions. The latter trigger a conformational change in the protein’s <em>C</em>-terminus, involving its ATG2C domain acting as sensor of damage-induced lipid packing defects. We show that ER-lysosome contacts formed by VPS13C provide critical binding platforms for OSBP/ORPs to enable efficient ER wrapping of damaged lysosomes. A chemical approach to assess directional ER-to-lysosome lipid transport revealed that VPS13C is essential for large-scale lipid delivery to acutely damaged lysosomes to facilitate their repair. Our findings offer new mechanistic insights into how loss-of-function mutations in <em>VPS13C</em> may enhance the risk of Parkinson’s disease.</p><p><br></p><p>This study contains shotgun lipidomics data from HeLa cells treated with L-leucyl-L-leucine methyl ester (LLOMe), a lysosomotropic agent that induces lysosomal membrane damage. Lipid profiles were obtained from both whole-cell lysates and isolated lysosomal fractions. Lipids were extracted and quantified by mass spectrometry-based shotgun lipidomics.</p>
2026-07-03 | MTBLS14737 | MetaboLights
Project description:Plasma membrane damage-dependent senescence is a novel senescence subtype. Here, we compare the time-resolved proteomic profiles of plasma membrane damage-dependent senescence, DNA damage-dependent senescence, and replicative senescence to find the major differences between the senescence subtypes.
2024-12-20 | PXD047976 | JPOST Repository
Project description:ROSALIND protects the mitochondrial translational machinery from oxidative damage
| PRJNA1049779 | ENA
Project description:Reprogrammed lipid metabolism protects inner nuclear membrane against unsaturated fat
| PRJNA659650 | ENA
Project description:Lysosomal membrane permeabilization (LMP) or lysosomal membrane damage is commonly associated with aging and age-related diseases. In searching for cellular mechanisms in response to LMP, we used a proteomic approach to identify proteins enriched on damaged lysosomes. This unbiased approach identified a new phosphoinositide signaling pathway triggered by LMP to mediate rapid lysosomal repair. Specifically, LMP induces fast lysosomal recruitment of PI4K2A which generates high levels of the lipid messenger phosphatidylinositol-4-phosphate (PtdIns4P) on damaged lysosomes. Lysosomal PtdIns4P in turn recruits multiple oxysterol-binding protein (OSBP)-related protein (ORP) family members, including ORP9, ORP10, and ORP11, to orchestrate extensive membrane contact sites (MCSs) between damaged lysosomes and the endoplasmic reticulum (ER). The ORPs subsequently catalyze robust ER-to-lysosomal transport of phosphatidylserine (PS), which is critical for rapid lysosomal repair. The lipid transporter ATG2 is also recruited to damaged lysosomes, activated by PS, and is essential for rapid lysosomal repair. Our findings identify a phosphoinositide-dependent membrane tethering and lipid transport (PITT) pathway essential for the maintenance of lysosomal membrane integrity, with important implications for a wide range of diseases characterized by impaired lysosomal function.
2022-09-07 | PXD028852 | Pride