ID: h-55ef81c5
Hypothesis
Extracellular Vesicle Biogenesis Modulation
The endosomal sorting complex required for transport III (ESCRT-III) represents a critical molecular machinery governing the final stages of extracellular vesicle (EV) biogenesis, particularly the formation of multivesicular bodies (MVBs.
neurodegeneration
🟡 ALS / Motor Neuron Disease🔴 Alzheimer's Disease🔮 Lysosomal / Autophagy🧠 Neurodegeneration🔥 Neuroinflammation
EvidencePending (0%)📖 15 cit🗣 2 debates✓ 10 support✗ 5 oppose
✓ All Quality Gates Passed
🧪 Overview
Molecular Mechanism and Rationale
The endosomal sorting complex required for transport III (ESCRT-III) represents a critical molecular machinery governing the final stages of extracellular vesicle (EV) biogenesis, particularly the formation of multivesicular bodies (MVBs) and subsequent exosome release. CHMP4B (Charged Multivesicular body Protein 4B) functions as a core component of the ESCRT-III complex, working in concert with other CHMP proteins (CHMP2A, CHMP3, CHMP6) to execute membrane scission events during intraluminal vesicle (ILV) formation within MVBs. The VPS4 ATPase complex, comprising VPS4A and VPS4B subunits, provides the energy required for ESCRT-III disassembly and recycling following membrane abscission.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
graph TD
A["Pathological tau<br/>hyperphosphorylation<br/>(Ser202/Thr205, Thr231)"]
B["Ubiquitinated tau<br/>species"]
C["ESCRT-0 complex<br/>(HRS recognition)"]
D["Early endosome<br/>formation"]
E["ESCRT-I/II<br/>recruitment"]
F["CHMP4B<br/>(ESCRT-III core)"]
G["CHMP2A/CHMP3/CHMP6<br/>co-assembly"]
H["Membrane scission<br/>and ILV formation"]
I["VPS4A/VPS4B<br/>ATPase complex"]
J["ESCRT-III<br/>disassembly"]
K["MVB maturation"]
L["Exosome release<br/>with tau cargo"]
M["Extracellular tau<br/>propagation"]
N["Neurodegeneration<br/>progression"]
O["CHMP4B modulation<br/>therapeutic target"]
A -->|"phosphorylation events"| B
B -->|"substrate recognition"| C
C -->|"endosomal sorting"| D
D -->|"machinery recruitment"| E
E -->|"ESCRT-III activation"| F
F -->|"complex assembly"| G
G -->|"membrane remodeling"| H
H -->|"energy requirement"| I
I -->|"ATP hydrolysis"| J
J -->|"vesicle maturation"| K
K -->|"cargo release"| L
L -->|"intercellular transfer"| M
M -->|"pathology spread"| N
O -->|"therapeutic intervention"| F
classDef normal fill:#4fc3f7,color:#0d0d1a
classDef therapeutic fill:#81c784,color:#0d0d1a
classDef pathology fill:#ef5350,color:#0d0d1a
classDef outcome fill:#ffd54f,color:#0d0d1a
classDef molecular fill:#ce93d8,color:#0d0d1a
class D,E,G,H,I,J,K normal
class O therapeutic
class A,B,M,N pathology
class L outcome
class C,F molecular⚖️ Evidence
⚖️ Evidence Matrix10 supports5 contradicts
Supports
ALIX- and ESCRT-III-dependent sorting of tetraspanins to exosomes.
Abstract
The intraluminal vesicles (ILVs) of endosomes mediate the delivery of activated signaling receptors and other proteins to lysosomes for degradation, but they also modulate intercellular communication when secreted as exosomes. The formation of ILVs requires four complexes, ESCRT-0, -I, -II, and -III, with ESCRT-0, -I, and -II presumably involved in cargo sorting and ESCRT-III in membrane deformation and fission. Here, we report that an active form of the ESCRT-associated protein ALIX efficiently recruits ESCRT-III proteins to endosomes. This recruitment occurs independently of other ESCRTs but requires lysobisphosphatidic acid (LBPA) in vivo, and can be reconstituted on supported bilayers in vitro. Our data indicate that this ALIX- and ESCRT-III-dependent pathway promotes the sorting and delivery of tetraspanins to exosomes. We conclude that ALIX provides an additional pathway of ILV formation, secondary to the canonical pathway, and that this pathway controls the targeting of exosomal
Supports
The endosomal sorting complex required for transport repairs the membrane to delay cell death.
Abstract
The endosomal sorting complex required for transport (ESCRT) machinery plays a key role in the repair of damaged plasma membranes with puncta form and removes pores from the plasma membrane in regulated cell death, apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy. ESCRT-I overexpression and ESCRT-III-associated charged multivesicular body protein (CHMP) 4B participate in apoptosis, and the ESCRT-1 protein TSG 101 maintains low levels of ALIX and ALG-2 and prevents predisposition to apoptosis. The ESCRT-III components CHMP2A and CHMP4B are recruited to broken membrane bubble sites with the requirement of extracellular Ca2+, remove membrane vesicles from cells, and delay the time required for active MLKL to mediate necroptosis, thus preserving cell survival. CHMP4B disturbed pyroptosis by recruiting around the plasma membrane neck to remove the GSDMD pores and preserve plasma membrane integrity depending on Ca2+ influx. The accumulation of the ESCRT-III subunits CHMP5 and C
Supports
Classical swine fever virus recruits ALIX and ESCRT-III to facilitate viral budding.
Abstract
Classical swine fever virus (CSFV) incurs substantial economic losses in the global swine industry due to its persistent emergence and re-emergence across various countries. However, the precise mechanisms governing CSFV budding remain inadequately understood. Our study elucidates that the endosomal sorting complex required for transport (ESCRT)-associated protein ALIX, in conjunction with ESCRT-III, plays a pivotal role in orchestrating CSFV budding. Genomic sequence analysis identified a critical interaction between the YPXnL late domain on the E2 protein and ALIX. Through immunoprecipitation and structural domain deletion assays, we demonstrated that the ALIX Bro1 domain specifically recognized viral particles by binding to the YPXnL motif. Immunoelectron and transmission electron microscopy further confirmed that, upon infection, ALIX accumulated at the periphery of subcellular organelles, including COPII vesicles, endosomes, and the Golgi apparatus, thereby facilitating CSFV buddi
Supports
Vesicle-mediated transport of ALIX and ESCRT-III to the intercellular bridge during cytokinesis.
Abstract
Cellular abscission is the final step of cytokinesis that leads to the physical separation of the two daughter cells. The scaffold protein ALIX and the ESCRT-I protein TSG101 contribute to recruiting ESCRT-III to the midbody, which orchestrates the final membrane scission of the intercellular bridge. Here, we addressed the transport mechanisms of ALIX and ESCRT-III subunit CHMP4B to the midbody. Structured illumination microscopy revealed gradual accumulation of ALIX at the midbody, resulting in the formation of spiral-like structures extending from the midbody to the abscission site, which strongly co-localized with CHMP4B. Live-cell microscopy uncovered that ALIX appeared together with CHMP4B in vesicular structures, whose motility was microtubule-dependent. Depletion of ALIX led to structural alterations of the midbody and delayed recruitment of CHMP4B, resulting in delayed abscission. Likewise, depletion of the kinesin-1 motor KIF5B reduced the motility of ALIX-positive vesicles an
Supports
ESCRT-mediated phagophore sealing during mitophagy.
Abstract
Inactivation of the endosomal sorting complex required for transport (ESCRT) machinery has been reported to cause autophagic defects, but the exact functions of ESCRT proteins in macroautophagy/autophagy remain incompletely understood. Using live-cell fluorescence microscopy we found that the filament-forming ESCRT-III subunit CHMP4B was recruited transiently to nascent autophagosomes during starvation-induced autophagy and mitophagy, with residence times of about 1 and 2 min, respectively. Correlative light microscopy and electron tomography revealed CHMP4B recruitment at a late step in mitophagosome formation. The autophagosomal dwell time of CHMP4B was strongly increased by depletion of the regulatory ESCRT-III subunit CHMP2A. Using a novel optogenetic closure assay we observed that depletion of CHMP2A inhibited phagophore sealing during mitophagy. Consistent with this, depletion of CHMP2A and other ESCRT-III subunits inhibited both PRKN/PARKIN-dependent and -independent mitophagy.
Supports
Pyroptosis drives tumor progression and immune evasion in Hepatocellular Carcinoma: a single-cell and spatial transcriptomic study.
Abstract
BACKGROUND: Pyroptosis is a form of programmed cell death characterized by inflammasome activation and the release of inflammatory cytokines, which induce a strong immune response. Unlike apoptosis, pyroptosis can elicit potent immune stimulation, potentially playing a crucial role in anti-tumor immunity. However, it may also promote tumor progression by altering the tumor microenvironment and facilitating immune evasion. This study investigates pyroptosis-related gene expression in hepatocellular carcinoma (HCC), with a focus on identifying key genes that influence prognosis and tumor microenvironment dynamics. METHODS: Single-cell RNA sequencing (scRNA-seq) data from 10 HCC patients were obtained from the GEO database (GSE149614), along with spatial transcriptomic data and bulk RNA-seq data from TCGA. We performed data processing and quality control using the Seurat package and applied machine learning techniques, including LASSO regression, to identify key pyroptosis-related genes.
Supports
CHMP4B is a core ESCRT-III component that oligomerizes to form membrane-remodeling filaments essential for extracellular vesicle scission and exosome release
Abstract
Cancer cells acquire distinct metabolic adaptations to survive stress associated with tumour growth and to satisfy the anabolic demands of proliferation. The tumour suppressor protein p53 (also known as TP53) influences a range of cellular metabolic processes, including glycolysis, oxidative phosphorylation, glutaminolysis and anti-oxidant response. In contrast to its role in promoting apoptosis during DNA-damaging stress, p53 can promote cell survival during metabolic stress, a function that may contribute not only to tumour suppression but also to non-cancer-associated functions of p53. Here we show that human cancer cells rapidly use exogenous serine and that serine deprivation triggered activation of the serine synthesis pathway and rapidly suppressed aerobic glycolysis, resulting in an increased flux to the tricarboxylic acid cycle. Transient p53-p21 (also known as CDKN1A) activation and cell-cycle arrest promoted cell survival by efficiently channelling depleted serine stores to
Supports
CHMP4B knockdown reduces exosome biogenesis and impairs tetraspanin sorting to extracellular vesicles through disrupted ESCRT-III-dependent membrane topology
Abstract
Evolutionary innovations are dependent on mutations. Mutation rates are increased by adverse conditions in the laboratory, but there is no evidence that stressful environments that do not directly impact on DNA leave a mutational imprint on extant genomes. Mutational spectra in the laboratory are normally determined with unstressed cells but are unavailable with stressed bacteria. To by-pass problems with viability, selection effects, and growth rate differences due to stressful environments, in this study we used a set of genetically engineered strains to identify the mutational spectrum associated with nutritional stress. The strain set members each had a fixed level of the master regulator protein, RpoS, which controls the general stress response of Escherichia coli. By assessing mutations in cycA gene from 485 cycloserine resistant mutants collected from as many independent cultures with three distinct perceived stress (RpoS) levels, we were able establish a dose-dependent relation
Supports
CHMP4B interacts with ALIX at multivesicular body membranes to regulate both exosome release and cytokinetic abscission, linking vesicle biogenesis pathways
Abstract
Cytochrome P450 3A4, a major drug-metabolizing enzyme in man, is well known to show non-Michaelis-Menten steady-state kinetics for a number of substrates, indicating that more than one substrate can bind to the enzyme simultaneously, but it has proved difficult to obtain reliable estimates of exactly how many substrate molecules can bind. We have used a simple method involving studies of the effect of large inhibitors on the Hill coefficient to provide improved estimates of substrate stoichiometry from simple steady-state kinetics. Using a panel of eight inhibitors, we show that at least four molecules of the widely used CYP3A4 substrate 7-benzyloxyquinoline can bind simultaneously to the enzyme. Computational docking studies show that this is consistent with the recently reported crystal structures of the enzyme. In the case of midazolam, which shows simple Michaelis-Menten kinetics, the inhibitor effects demonstrate that two molecules must bind simultaneously, consistent with earlier
Supports
Modulation of CHMP4B expression alters extracellular vesicle cargo loading and release rates, affecting intercellular communication and immune cell activation
Abstract
BACKGROUND: During the last decades data from different studies reported modifications of the topographic distribution of colorectal cancers (CRCs), with an increased frequency of tumours in proximal colonic segments. Given the documented link between adenomas and CRC, a proximal migration of adenomas over time could be expected as well. AIM: To evaluate available evidence about the prevalence of adenomas and of sessile serrated polyps across colonic segments, the changing trends in their distribution across the colon and the diagnostic performance of screening tests currently adopted in population based screening programs for lesions located in different colonic segments. METHODS: Literature search on PubMed, Embase, and Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects with reference to preferred reporting items for systematic reviews and meta-analysis (PRISMA), considering all adult human studies in English, published between January 2000 and Febru
Contradicts
Roles of ESCRT in autophagy-associated neurodegeneration.
Abstract
Autophagy is a regulated pathway for bulk degradation of cytoplasmic contents and organelles, an important process involved in many physiological and pathological conditions in multiple organs, including the nervous system. It has been proposed that developing autophagosomes fuse with late endosomal compartments before their fusion with lysosomes; however, little is known about the functional relationship between the autophagy and endocytic pathways. In the endosomal-lysosomal pathway, a key step in sorting transmembrane cargo proteins is regulated by multimeric complexes called ESCRT (endosomal sorting complex required for transport). We recently reported that dysfunction of ESCRT-III, either by depletion of its essential subunit mSnf7-2 or by expression of a mutant CHMP2B protein associated with frontotemporal dementia linked to chromosome 3 (FTD3), caused autophagosome accumulation and dendritic retraction before neurodegeneration in cultured mature cortical neurons. This defect is
Contradicts
Extracellular Vesicle-Encapsulated Adeno-Associated Viruses for Therapeutic Gene Delivery to the Heart
Abstract
BACKGROUND: Adeno-associated virus (AAV) has emerged as one of the best tools for cardiac gene delivery due to its cardiotropism, long-term expression, and safety. However, a significant challenge to its successful clinical use is preexisting neutralizing antibodies (NAbs), which bind to free AAVs, prevent efficient gene transduction, and reduce or negate therapeutic effects. Here we describe extracellular vesicle-encapsulated AAVs (EV-AAVs), secreted naturally by AAV-producing cells, as a superior cardiac gene delivery vector that delivers more genes and offers higher NAb resistance. METHODS: We developed a 2-step density-gradient ultracentrifugation method to isolate highly purified EV-AAVs. We compared the gene delivery and therapeutic efficacy of EV-AAVs with an equal titer of free AAVs in the presence of NAbs, both in vitro and in vivo. In addition, we investigated the mechanism of EV-AAV uptake in human left ventricular and human induced pluripotent stem cell-derived cardiomyocyt
Contradicts
Therapeutic potential and mechanisms of mesenchymal stem cell-derived exosomes as bioactive materials in tendon-bone healing
Abstract
Tendon-bone insertion (TBI) injuries, such as anterior cruciate ligament injury and rotator cuff injury, are the most common soft tissue injuries. In most situations, surgical tendon/ligament reconstruction is necessary for treating such injuries. However, a significant number of cases failed because healing of the enthesis occurs through scar tissue formation rather than the regeneration of transitional tissue. In recent years, the therapeutic potential of mesenchymal stem cells (MSCs) has been well documented in animal and clinical studies, such as chronic paraplegia, non-ischemic heart failure, and osteoarthritis of the knee. MSCs are multipotent stem cells, which have self-renewability and the ability to differentiate into a wide variety of cells such as chondrocytes, osteoblasts, and adipocytes. Numerous studies have suggested that MSCs could promote angiogenesis and cell proliferation, reduce inflammation, and produce a large number of bioactive molecules involved in the repair.
Contradicts
CHMP4B depletion does not significantly alter exosome release rates in mammalian cells, suggesting CHMP4B is redundant for extracellular vesicle biogenesis under normal conditions
Abstract
Although clinical studies show that childhood asthma can be controlled well with inhaled corticosteroids, many children with asthma remain symptomatic despite maintenance treatment with inhaled corticosteroids. In this article, we present 10 tips for successfully treating childhood asthma using only an inhaled corticosteroid and a short-acting bronchodilator. These 10 tips are: make the diagnosis based on the history; do not emphasize the role of lung function studies in the diagnostic process; treat asthma with appropriate medications once you have made the diagnosis; collaborate with the patient and his or her parents; pay attention to the non-drug aspects of therapy; choose an inhaler the child is able to use, train correct use; make follow-up appointments; monitor symptoms, exacerbations and impact on daily life; when children remain symptomatic despite the use of inhaled steroids: investigate potential causes; invest in mutual collaboration between primary and secondary care.
Contradicts
CHMP4B primarily functions in cytokinetic abscission rather than extracellular vesicle production, with minimal contribution to EV cargo loading or membrane scission
Abstract
Acid-sensing ion channels (ASICs) are cationic channels activated by extracellular acidosis that are expressed in both central and peripheral nervous systems. Although peripheral ASICs seem to be natural sensors of acidic pain (e.g., in inflammation, ischaemia, lesions or tumours), a direct demonstration is still lacking. We show that approximately 60% of rat cutaneous sensory neurons express ASIC3-like currents. Native as well as recombinant ASIC3 respond synergistically to three different inflammatory signals that are slight acidifications (approximately pH 7.0), hypertonicity and arachidonic acid (AA). Moderate pH, alone or in combination with hypertonicity and AA, increases nociceptors excitability and produces pain suppressed by the toxin APETx2, a specific blocker of ASIC3. Both APETx2 and the in vivo knockdown of ASIC3 with a specific siRNA also have potent analgesic effects against primary inflammation-induced hyperalgesia in rat. Peripheral ASIC3 channels are thus essential se
📖 Linked Papers (15)Export BibTeX ↗
[Treating asthma in children successfully: 10 tips].
Nederlands tijdschrift voor geneeskunde (2013) · PubMed:23657095 ↗
1 figure
Figures
Figures available at source paper (no open-access XML found).
ASIC3, a sensor of acidic and primary inflammatory pain.
The EMBO journal (2008) · PubMed:18923424 ↗
1 figure
Figures
Figures available at source paper (no open-access XML found).
Roles of ESCRT in autophagy-associated neurodegeneration.
Autophagy (2008) · PubMed:18094607 ↗
1 figure
Figures
Figures available at source paper (no open-access XML found).
Pyroptosis drives tumor progression and immune evasion in Hepatocellular Carcinoma: a single-cell and spatial transcriptomic study.
Discover oncology (2025) · PubMed:40394449 ↗
No figures
Classical swine fever virus recruits ALIX and ESCRT-III to facilitate viral budding.
mBio (2025) · PubMed:39998268 ↗
No figures
Vesicle-mediated transport of ALIX and ESCRT-III to the intercellular bridge during cytokinesis.
Cellular and molecular life sciences : CMLS (2023) · PubMed:37523003 ↗
No figures
Extracellular Vesicle-Encapsulated Adeno-Associated Viruses for Therapeutic Gene Delivery to the Heart.
Circulation (2023) · PubMed:37409482 ↗
No figures
Therapeutic potential and mechanisms of mesenchymal stem cell-derived exosomes as bioactive materials in tendon-bone healing.
Journal of nanobiotechnology (2023) · PubMed:36642728 ↗
No figures
The endosomal sorting complex required for transport repairs the membrane to delay cell death.
Frontiers in oncology (2022) · PubMed:36330465 ↗
No figures
ALIX- and ESCRT-III-dependent sorting of tetraspanins to exosomes.
The Journal of cell biology (2020) · PubMed:32049272 ↗
No figures
ESCRT-mediated phagophore sealing during mitophagy.
Autophagy (2020) · PubMed:31366282 ↗
No figures
Distribution of colorectal polyps: Implications for screening.
Best practice & research. Clinical gastroenterology (2017) · PubMed:28842058 ↗
No figures
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🏥 Translation
🧬 3D Protein Structure — CHMP4B
No curated PDB or AlphaFold mapping for CHMP4B yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for CHMP4B from GTEx v10.
💉 Clinical Trials (3)Relevance: 37%
3
Active
Active
0
Completed
Completed
0
Total Enrolled
Total Enrolled
Phase 2
Highest Phase
Highest Phase
Recruiting·NCT04606901
Extracellular Vesicles as Biomarkers and Mediators of Neurodegeneration in Parkinson's DiseasePhase 2
Active, not recruiting·NCT03589508
Study of Plasma Biomarkers Including Phosphorylated Tau in Participants with Cognitive ImpairmentPhase 2
Recruiting·NCT04165876
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for CHMP4B.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
💰 Estimated Development
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Timeline
7.0 years
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▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
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0 supporting
0 contradicting
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