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ESCRT-mediated machinery directly drives cardiac T-tubule formation

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE275879 | GEO | 2026/03/03

REPOSITORIES: GEO

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ESCRT-mediated machinery directly drives cardiac T-tubule formation

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). We demonstrate that Chmp4b is essential for T-tubule formation, a process dependent on the ESCRT-I component Tsg101. Our results uncover that the spatiotemporal organization of ESCRT can orchestrate invaginations of cardiomyocyte plasma membrane.

2026-03-03 | GSE276054 | GEO

Systematic analysis of ESCRT mutants reveals an essential function for the MVB pathway in amino acid recycling.

Project description:The ESCRT machinery drives the multivesicular body (MVB) pathway in eukaryotic cells and thus is required for the degradation of ubiquitinated membrane proteins in lysosomes. To systematically characterize how cells respond to loss of ESCRT function, we used quantitative proteomics and gene expression profiling in yeast. We find that ESCRT mutants display severe defects in amino acid homeostasis, resulting in lower levels of free intracellular amino acids. This deficit renders the growth of ESCRT mutants highly sensitive to nutrient limitation. Further proteomic analysis revealed that the MVB pathway essentially contributes to proteome remodeling under nutrient limitation. The rapid decline of protein synthesis upon starvation no longer enables ESCRT mutants to complete their cell cycle and properly enter a quiescent state, which strongly affects their long-term survival. Thus, the MVB pathway functions to selectively down-regulate integral membrane proteins and, together with autophagy and proteasomal degradation, considerably contributes to amino acid recycling. We used microarrays to identify gene expression changes between delta VPS4 knock out and wild type Saccharomyces cerevisiae strains

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Components of the ESCRT machinery act downstream of MLKL to regulate necroptotic cell death and its consequences

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

ESCRT-I controls lysosomal membrane protein homeostasis and restricts MCOLN1-dependent TFEB/TFE3 signaling.

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

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The Flemmingsome reveals an ESCRT-to-membrane coupling required for cytokinesis

Project description:Cytokinesis requires the constriction of ESCRT-III filaments on the midbody side, where abscission occurs. After ESCRT recruitment at the midbody, it is not known how the ESCRT-III machinery localizes to the abscission site. We obtained the proteome of intact, post-abscission midbodies (Flemmingsome) and revealed enriched proteins in this organelle. We propose that the ESCRT-III machinery must be physically coupled to a membrane protein at the cytokinetic abscission site for productive scission, revealing novel common requirements in cytokinesis, exosome formation and retroviral budding.

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The ESCRT-III protein CHMP1A mediates secretion of sonic hedgehog on a novel class of extracellular vesicles

Project description:Extracellular vesicles (EVs) enable cell-to-cell communication in the nervous system essential for development and adult function. Endosomal Sorting Complex Required for Transport (ESCRT) complex proteins regulate EV formation and release. Recent work shows loss of function (LOF) mutations in, CHMP1A, which encodes one ESCRT-III member, cause autosomal recessive microcephaly with pontocerebellar hypoplasia in humans (Mochida et al., 2012). Here we show CHMP1A is required for maintenance of progenitors in human cerebral organoids and that mouse Chmp1a is required for progenitor proliferation in cortex and cerebellum and specifically for sonic hedgehog (SHH) mediated proliferation through SHH secretion. CHMP1A mutation reduces intraluminal vesicle (ILV) formation in multivesicular bodies (MVBs), and EV release. SHH protein is present on a subset of EVs marked by a unique set of proteins we call ART-EVs. CHMP1A’s requirement in formation of ART-EVs and other EVs provides a model to elucidate EV functions in multiple brain processes.

2018-06-16 | GSE115867 | GEO

USP8 coordinates ESCRT-mediated membrane repair, xenophagy, and oxidative stress responses during Mycobacterium tuberculosis infection

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2024-08-07 | GSE240372 | GEO

Misregulation of alternative splicing of BIN1 leads to T-tubule alterations and muscle weakness in myotonic dystrophy

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

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2022-12-20 | PXD031515 | Pride

Accessory ESCRT-III proteins are conserved and selective regulators of Rab11a-exosome formation

Project description:Exosomes are secreted nanovesicles with potent signalling activity that are initially formed as intraluminal vesicles (ILVs) in late Rab7-positive multivesicular endosomes, and also in recycling Rab11a-positive endosomes, particularly under some forms of nutrient stress. The core proteins of the Endosomal Sorting Complex Required for Transport (ESCRT) participate in exosome biogenesis and ILV-mediated destruction of ubiquitinylated cargos. Accessory ESCRT-III components have reported roles in ESCRT-III-mediated vesicle scission, but their precise functions are poorly defined. They frequently only appear essential under stress. Comparative proteomics analysis of human small extracellular vesicles revealed that accessory ESCRT-III proteins, CHMP1A, CHMP1B, CHMP5 and IST1, are increased in Rab11a-enriched exosome preparations. We show that these proteins are required to form ILVs in Drosophila secondary cell recycling endosomes, but unlike core ESCRTs, they are not involved in degradation of ubiquitinylated proteins in late endosomes. Furthermore, CHMP5 knockdown in human HCT116 colorectal cancer cells selectively inhibits Rab11a-exosome production. Accessory ESCRT-III knockdown suppresses seminal fluid-mediated reproductive signalling by secondary cells and the growth-promoting activity of Rab11a-exosome-containing EVs from HCT116 cells. We conclude that accessory ESCRT-III components have a specific, ubiquitin-independent role in Rab11a-exosome generation, a mechanism that might be targeted to selectively block pro-tumorigenic activities of these vesicles in cancer.

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