ESCRT-mediated machinery directly drives cardiac T-tubule formation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE276054 | GEO | 2026/03/03
REPOSITORIES: GEO
Similar Datasets
Project description:Cardiac transverse tubules (T-tubules) are regular spaced plasma membrane invaginations that play an essential role in establishing excitation-contraction coupling of cardiomyocytes, yet the molecular machinery that controls T-tubule formation remains elusive. The endosomal sorting complex required for transport (ESCRT) proteins are involved in a variety of cellular events primarily through regulating membrane deformation in a reverse topology mode (budding away from cytosol). Strikingly, we find ESCRT directly controls the inward budding of cardiomyocyte plasma membrane to form T-tubules. Visualization of postnatal cardiomyocytes uncovers the gradual localization of charged multivesicular body protein 4b (Chmp4b), the key ESCRT-III filament component, to T-tubules.
2026-03-03 | GSE275879 | GEO
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:Myotonic dystrophes (DM), the most common adult muscular dystrophy, are the first recognized examples of RNA-mediated diseases in which expression of mutant RNAs containing expanded CUG or CCUG repeats interfere with the splicing of other mRNAs. Using whole-genome microarrays, we found that alternative splicing of the BIN1 mRNA is altered in DM skeletal muscle tissues, resulting in the expression of an inactive form of BIN1 deprived of phosphoinositide-binding and membrane-tubulating activities. BIN1 is involved in tubular invaginations of the plasma membrane and is essential for biogenesis of the muscle T-tubules, which are specialized skeletal muscle membrane structures essential to correct excitation-contraction (E-C) coupling. Mutations in the BIN1 gene cause centronuclear myopathy (CNM) that shares some histopathological features with DM, and both diseases are characterized by muscle weakness. Consistent with a loss-of-function of BIN1, muscle T-tubules were altered in DM patients, and membrane tubulation was restored upon expression of the correct splicing form of BIN1 in DM muscle cells. By deciphering the mechanism of BIN1 splicing mis-regulation we demonstrate that the splicing regulator, MBNL1, which is sequestered by expanded CUG and CCUG in DM, binds the BIN1 pre-mRNA and regulates directly its alternative splicing. Finally, reproducing BIN1 splicing alteration in mice is sufficient to reproduce the DM features of T-tubule alterations and muscle weakness. We propose that alteration of BIN1 alternative splicing regulation leads to muscle weakness, a predominant pathological feature of DM. Exon-Array analysis of control and CDM1 muscle primary cultures 10 days of differentiation
2011-05-26 | E-GEOD-21795 | biostudies-arrayexpress
Project description:The activation of Mixed Lineage Kinase-Like (MLKL) by Receptor Interacting Protein Kinase-3 (RIPK3) results in plasma membrane (PM) disruption and a form of regulated necrosis, called necroptosis. Here we show that during necroptosis, MLKL-dependent calcium (Ca++) influx and phosphatidylserine (PS) exposure on the outer leaflet of the plasma membrane preceded loss of PM integrity. Activation of MLKL results in the generation of broken, PM “bubbles” with exposed PS that are released from the surface of the otherwise intact cell. Components of the ESCRT machinery are required for formation of these bubbles, and act to sustain survival of the cell when MLKL activation is limited or reversed. Under conditions of necroptotic cell death, ESCRT controls the duration of plasma membrane integrity. As a consequence of the action of ESCRT, cells undergoing necroptosis can express chemokines and other regulatory molecules, and promote antigenic cross-priming of CD8+ T cells.
2017-06-16 | GSE85660 | GEO
Project description:Myotonic dystrophes (DM), the most common adult muscular dystrophy, are the first recognized examples of RNA-mediated diseases in which expression of mutant RNAs containing expanded CUG or CCUG repeats interfere with the splicing of other mRNAs. Using whole-genome microarrays, we found that alternative splicing of the BIN1 mRNA is altered in DM skeletal muscle tissues, resulting in the expression of an inactive form of BIN1 deprived of phosphoinositide-binding and membrane-tubulating activities. BIN1 is involved in tubular invaginations of the plasma membrane and is essential for biogenesis of the muscle T-tubules, which are specialized skeletal muscle membrane structures essential to correct excitation-contraction (E-C) coupling. Mutations in the BIN1 gene cause centronuclear myopathy (CNM) that shares some histopathological features with DM, and both diseases are characterized by muscle weakness. Consistent with a loss-of-function of BIN1, muscle T-tubules were altered in DM patients, and membrane tubulation was restored upon expression of the correct splicing form of BIN1 in DM muscle cells. By deciphering the mechanism of BIN1 splicing mis-regulation we demonstrate that the splicing regulator, MBNL1, which is sequestered by expanded CUG and CCUG in DM, binds the BIN1 pre-mRNA and regulates directly its alternative splicing. Finally, reproducing BIN1 splicing alteration in mice is sufficient to reproduce the DM features of T-tubule alterations and muscle weakness. We propose that alteration of BIN1 alternative splicing regulation leads to muscle weakness, a predominant pathological feature of DM.
2011-05-26 | GSE21795 | GEO
Project description:Within the endolysosomal pathway in mammalian cells, ESCRT complexes facilitate degradation of membrane proteins from limiting membranes of late endosomes. Recent studies revealed that yeast ESCRT proteins also sort for degradation, ubiquitinated proteins from vacuolar membrane. However, whether mammalian ESCRTs perform similar function at lysosomes remained unknown. Here, we studied the involvement of mammalian ESCRT-I in maintaining lysosomal membrane homeostasis and its implication in lysosome-related signaling. We show that ESCRT-I restricts the size of lysosomes and promotes degradation of lysosomal Ca2+ channel, MCOLN1 protein. ESCRT-I depletion induced transcriptional response related to MiT-TFE signaling and cholesterol biosynthesis, pointing to lysosomal dysfunction. The lack of ESCRT-I promoted abnormal cholesterol accumulation on lysosomes and activated TFEB/TFE3 transcription factors in Ca2+-MCOLN1-dependent, but lipid-independent manner. Hence, our study provides evidence that ESCRT-I maintains lysosomal homeostasis and elucidates MiT-TFE regulatory mechanism activated in response to ESCRT-I deprivation
2022-03-28 | GSE178665 | GEO
Project description:Abscission is the final stage of cytokinesis whereby the midbody, a thin intercellular bridge, is resolved to separate the daughter cells. Cytokinetic abscission is mediated by the Endosomal Sorting Complex Required for Transport (ESCRT), a conserved membrane remodelling machinery. The midbody organiser CEP55 recruits early acting ESCRT factors such as ESCRT-I and ALIX, which subsequently initiate the formation of ESCRT-III polymers that sever the midbody. We now identify UMAD1 as an ESCRT-I subunit that facilitates abscission. UMAD1 selectively associates with VPS37C and VPS37B, supporting the formation of cytokinesis-specific ESCRT-I assemblies. TSG101 recruits UMAD1 to the site of midbody abscission, to stabilise the CEP55/ESCRT-I interaction. We further demonstrate that the UMAD1/ESCRT-I interaction facilitates the final step of cytokinesis. Paradoxically, UMAD1 and ALIX co-depletion has synergistic effects on abscission whilst ESCRT-III recruitment to the midbody is not inhibited. Importantly, we find that both UMAD1 and ALIX are required for the dynamic exchange of ESCRT-III subunits at the midbody. Therefore, UMAD1 reveals a key functional connection between ESCRT-I and ESCRT-III that is required for cytokinesis.
2023-08-04 | PXD043940 | Pride
Project description:ESCRT-mediated machinery directly drives cardiac T-tubule formation
| PRJNA1153460 | ENA
Project description:ESCRT-mediated machinery directly drives cardiac T-tubule formation
| PRJNA1154598 | ENA
Project description:Ample evidence points to the contribution of endocytosis to oncogenesis at the cellular level but molecular details still remain obscure. Our analysis of The Cancer Genome Atlas data involving cohorts of colorectal cancer (CRC) patients revealed stage-dependent alterations in the expression of 113 genes whose function is related to endocytic transport. Among differentially expressed genes we observed decreased transcription of VPS37B and to a lesser extent VPS37A in the advanced stages of CRC. One member of the Vps37 protein family (Vps37A, Vps37B, Vps37C, Vps37D) together with Tsg101 and Vps28 forms the core of the Endosomal Sorting Complex Required for Transport (ESCRT)-I mediating membrane-remodeling processes. Our analysis of an independent cohort of CRC patients corroborated that both VPS37B and VPS37A genes are downregulated at mRNA and protein levels. Depletion of both Vps37A and Vps37B proteins elicits multifaceted transcriptional alterations, including cell growth arrest and induction of sterile inflammatory response, which are further potentiated by co-silencing of VPS37C. Among analyzed silencing condition, concurrent knockdown of VPS37A, VPS37B and VPS37C evokes the greatest magnitude of p21-mediated inhibition of cell proliferation and activation of Nuclear Factor-κB and mitogen-activated protein kinases signaling. These processes are independently induced after co-silencing of VPS37 paralogs. We further show that the type and magnitude of transcriptional responses correlate with the ESCRT-I stability, which is differentially affected upon individual and concurrent Vps37 depletion. Our study provides novel insights into cancer cell biology by describing a cellular stress response that is associated with ESCRT-I destabilization, which might occur in CRC patients
2020-12-17 | GSE152195 | GEO