scholarly journals A charged multivesicular body protein (CHMP4B) is required for lens growth and differentiation

2019 ◽  
Vol 109 ◽  
pp. 16-27
Author(s):  
Yuefang Zhou ◽  
Thomas M. Bennett ◽  
Alan Shiels
Keyword(s):  
Multivesicular Body ◽  
Body Protein ◽  
Lens Growth

scholarly journals A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yuting Guan ◽  
Xiujie Liang ◽  
Ziyuan Ma ◽  
Hailong Hu ◽  
Hongbo Liu ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Association Studies ◽  
Genetic Locus ◽  
Human Kidney ◽  
Multivesicular Body ◽  
Chromatin Accessibility ◽  
Disease Genes ◽  
Genome Wide Association Studies ◽  
Disease Development ◽  
Body Protein

AbstractGenome-wide association studies (GWAS) have identified loci for kidney disease, but the causal variants, genes, and pathways remain unknown. Here we identify two kidney disease genes Dipeptidase 1 (DPEP1) and Charged Multivesicular Body Protein 1 A (CHMP1A) via the triangulation of kidney function GWAS, human kidney expression, and methylation quantitative trait loci. Using single-cell chromatin accessibility and genome editing, we fine map the region that controls the expression of both genes. Mouse genetic models demonstrate the causal roles of both genes in kidney disease. Cellular studies indicate that both Dpep1 and Chmp1a are important regulators of a single pathway, ferroptosis and lead to kidney disease development via altering cellular iron trafficking.

scholarly journals Multidimensional Analysis of the Role of Charged Multivesicular Body Protein 7 in Pan-Cancer

2021 ◽  
Vol Volume 14 ◽  
pp. 7907-7923
Author(s):  
Yu Guo ◽  
Jian Shi ◽  
Zeyun Zhao ◽  
Min Wang
Keyword(s):  
Multivesicular Body ◽  
Multidimensional Analysis ◽  
Body Protein ◽  
Pan Cancer

CHMP1 is a novel nuclear matrix protein affecting chromatin structure and cell-cycle progression

2001 ◽  
Vol 114 (13) ◽  
pp. 2383-2393 ◽  
Author(s):  
Daniel R. Stauffer ◽  
Tiffani L. Howard ◽  
Thihan Nyun ◽  
Stanley M. Hollenberg
Keyword(s):  
Gene Silencing ◽  
Nuclear Matrix ◽  
Cell Cycle Progression ◽  
Matrix Protein ◽  
Multivesicular Body ◽  
Polycomb Group ◽  
Condensed Chromatin ◽  
Stable Gene ◽  
Body Protein ◽  
Reading Frame

The Polycomb-group (PcG) is a diverse set of proteins required for maintenance of gene silencing during development. In a screen for conserved partners of the PcG protein Polycomblike (Pcl), we have identified a new protein, human CHMP1 (CHromatin Modifying Protein; CHarged Multivesicular body Protein), which is encoded by an alternative open reading frame in the PRSM1 gene and is conserved in both complex and simple eukaryotes. CHMP1 contains a predicted bipartite nuclear localization signal and distributes as distinct forms to the cytoplasm and the nuclear matrix in all cell lines tested. We have constructed a stable HEK293 cell line that inducibly overexpresses CHMP1 under ecdysone control. Overexpressed CHMP1 localizes to a punctate subnuclear pattern, encapsulating regions of nuclease-resistant, condensed chromatin. These novel structures are also frequently surrounded by increased histone H3 phosphorylation and acetylation. CHMP1 can recruit a PcG protein, BMI1, to these regions of condensed chromatin and can cooperate with co-expressed vertebrate Pcl in a Xenopus embryo PcG assay; this is consistent with a role in PcG function. In combination, these observations suggest that CHMP1 plays a role in stable gene silencing within the nucleus.

scholarly journals A cancer-associated polymorphism in ESCRT-III disrupts the abscission checkpoint and promotes genome instability

2018 ◽  
Vol 115 (38) ◽  
pp. E8900-E8908 ◽  
Author(s):  
Jessica B. A. Sadler ◽  
Dawn M. Wenzel ◽  
Lauren K. Williams ◽  
Marta Guindo-Martínez ◽  
Steven L. Alam ◽  
...  
Keyword(s):  
Cancer Susceptibility ◽  
Genome Instability ◽  
Multivesicular Body ◽  
Mitotic Checkpoint ◽  
Body Protein ◽  
Endosomal Sorting ◽  
Daughter Cells ◽  
Dna Replication Stress ◽  
Human Polymorphism ◽  
Mitotic Stress

Cytokinetic abscission facilitates the irreversible separation of daughter cells. This process requires the endosomal-sorting complexes required for transport (ESCRT) machinery and is tightly regulated by charged multivesicular body protein 4C (CHMP4C), an ESCRT-III subunit that engages the abscission checkpoint (NoCut) in response to mitotic problems such as persisting chromatin bridges within the midbody. Importantly, a human polymorphism in CHMP4C (rs35094336, CHMP4CT232) increases cancer susceptibility. Here, we explain the structural and functional basis for this cancer association: The CHMP4CT232 allele unwinds the C-terminal helix of CHMP4C, impairs binding to the early-acting ESCRT factor ALIX, and disrupts the abscission checkpoint. Cells expressing CHMP4CT232 exhibit increased levels of DNA damage and are sensitized to several conditions that increase chromosome missegregation, including DNA replication stress, inhibition of the mitotic checkpoint, and loss of p53. Our data demonstrate the biological importance of the abscission checkpoint and suggest that dysregulation of abscission by CHMP4CT232 may synergize with oncogene-induced mitotic stress to promote genomic instability and tumorigenesis.

Engagement of new castle disease virus (NDV) matrix (M) protein with charged multivesicular body protein (CHMP) 4 facilitates viral replication

2013 ◽  
Vol 171 (1) ◽  
pp. 80-88 ◽  
Author(s):  
Xiang Li ◽  
Xiaoqi Li ◽  
Hong Cao ◽  
Yongqiang Wang ◽  
Shijun J. Zheng
Keyword(s):  
Viral Replication ◽  
Disease Virus ◽  
Multivesicular Body ◽  
M Protein ◽  
Body Protein

scholarly journals Human CHMP6, a myristoylated ESCRT-III protein, interacts directly with an ESCRT-II component EAP20 and regulates endosomal cargo sorting

2005 ◽  
Vol 387 (1) ◽  
pp. 17-26 ◽  
Author(s):  
Chiharu YORIKAWA ◽  
Hideki SHIBATA ◽  
Satoshi WAGURI ◽  
Kazumi HATTA ◽  
Mio HORII ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
Membrane Surface ◽  
Consensus Sequence ◽  
Multivesicular Body ◽  
Body Protein ◽  
Hek 293 ◽  
Human Embryonic Kidney Cells ◽  
Vacuolar Protein ◽  
Cargo Sorting

CHMP6 (charged multivesicular body protein 6) is a human orthologue of yeast Vps (vacuolar protein sorting) 20, a component of ESCRT (endosomal sorting complex required for transport)-III. Various CHMP6 orthologues in organisms ranging from yeast to humans contain the N-myristoylation consensus sequence at each N-terminus. Metabolic labelling of HEK-293 (human embryonic kidney) cells showed the incorporation of [3H]myristate into CHMP6 fused C-terminally to GFP (green fluorescent protein) (CHMP6–GFP). Interactions of CHMP6 with another ESCRT-III component CHMP4b/Shax [Snf7 (sucrose non-fermenting 7) homologue associated with Alix] 1, one of three paralogues of human Vps32/Snf7, and with EAP20 (ELL-associated protein 20), a human counterpart of yeast Vps25 and component of ESCRT-II, were observed by co-immunoprecipitation of epitope-tagged proteins expressed in HEK-293 cells. The in vitro pull-down assays using their recombinant proteins purified from Escherichia coli demonstrated direct physical interactions which were mediated by the N-terminal basic half of CHMP6. Overexpressed CHMP6-GFP in HeLa cells exhibited a punctate distribution throughout the cytoplasm especially in the perinuclear area, as revealed by fluorescence microscopic analysis. Accumulation of LBPA (lysobisphosphatidic acid), a major phospholipid in internal vesicles of an MVB (multivesicular body), was observed in the CHMP6–GFP-localizing area. FLAG-tagged EAP20 distributed diffusely, but exhibited a punctate distribution on co-expression with CHMP6–GFP. Overexpression of CHMP6–GFP caused reduction of transferrin receptors on the plasma membrane surface, but caused their accumulation in the cytoplasm. Ubiquitinated proteins and endocytosed EGF continuously accumulated in CHMP6–GFP-expressing cells. These results suggest that CHMP6 acts as an acceptor for ESCRT-II on endosomal membranes and regulates cargo sorting.

Structure and function of ESCRT-III

2009 ◽  
Vol 37 (1) ◽  
pp. 156-160 ◽  
Author(s):  
Suman Lata ◽  
Guy Schoehn ◽  
Julianna Solomons ◽  
Ricardo Pires ◽  
Heinrich G. Göttlinger ◽  
...  
Keyword(s):  
Multivesicular Body ◽  
Multivesicular Bodies ◽  
Tubular Structures ◽  
Body Protein ◽  
Enveloped Viruses ◽  
Endosomal Sorting ◽  
Vacuolar Protein ◽  
And Function ◽  
Endosomal Vesicles

ESCRT-III (endosomal sorting complex required for transport III) is required for the formation and abscission of intraluminal endosomal vesicles, which gives rise to multivesicular bodies, budding of some enveloped viruses and cytokinesis. ESCRT-III is composed of 11 members in humans, which, except for one, correspond to the six ESCRT-III-like proteins in yeast. At least CHMP (charged multivesicular body protein) 2A and CHMP3 assemble into helical tubular structures that provide a platform for membrane interaction and VPS (vacuolar protein sorting) 4-catalysed effects leading to disassembly of ESCRT-III CHMP2A–CHMP3 polymers in vitro. Progress towards the understanding of the structures and function of ESCRT-III, its activation, its regulation by accessory factors and its role in abscission of membrane enveloped structures in concert with VPS4 are discussed.

Identification of novel downstream targets of platelet glycoprotein VI activation by differential proteome analysis: implications for thrombus formation

Blood ◽  
2010 ◽  
Vol 115 (20) ◽  
pp. 4102-4110 ◽  
Author(s):  
Christian Schulz ◽  
Nina V. Leuschen ◽  
Thomas Fröhlich ◽  
Michael Lorenz ◽  
Susanne Pfeiler ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activation ◽  
Membrane Trafficking ◽  
Thrombus Formation ◽  
Multivesicular Body ◽  
Platelet Glycoprotein ◽  
Body Protein ◽  
Glycoprotein Vi ◽  
Differentially Abundant Proteins ◽  
Platelet Proteins

Abstract Platelets play a key role in hemostasis and various diseases including arterial thrombosis. Glycoprotein VI (GPVI) mediates adhesion to collagen structures exposed at sites of vascular injury and subsequent platelet activation. We determined the effects of specific activation of GPVI on the human platelet proteome. Isolated human platelets were stimulated with an activating monoclonal antibody specific for GPVI. Platelet proteins were analyzed by 2-dimensional difference gel electrophoresis (2D-DIGE) and mass spectrometry. We identified 8 differentially abundant proteins associated with cell signaling, metabolism, organization and rearrangement of the cytoskeleton, and membrane trafficking. Differentially abundant proteins included aldose reductase (AR), beta-centractin, charged multivesicular body protein 3, Src substrate cortactin, ERp57, and pleckstrin. Importantly, GPVI-modulated protein abundance was functionally relevant. Correspondingly, AR enzyme activity significantly increased upon GPVI activation and inhibition of AR resulted in reduced platelet aggregation. Furthermore, ERp57 was released upon ligation of platelet GPVI and increased the activity of tissue factor, a major initiator of blood coagulation. In summary, GPVI activation results in differential changes in abundance of platelet proteins, including AR and ERp57, which support platelet aggregation and platelet-dependent coagulation. These results provide further insight into the mechanisms that underlie platelet activation through the GPVI receptor and may help to identify novel pharmacologic targets.

Abstract 3734: Differential Platelet Proteome Analysis Following Specific Activation Of Glycoprotein VI

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Christian Schulz ◽  
Nina V Leuschen ◽  
Thomas Fröhlich ◽  
Michael Lorenz ◽  
Georg J Arnold ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Membrane Trafficking ◽  
Proteome Analysis ◽  
Multivesicular Body ◽  
Healthy Human ◽  
Body Protein ◽  
2D Dige ◽  
Glycoprotein Vi ◽  
Platelet Proteome ◽  
Differentially Abundant Proteins

Background: Platelets play a key role in haemostasis and in the pathophysiology of various diseases including arterial thrombosis. Glycoprotein (GP)VI, the major platelet collagen receptor, mediates platelet activation and firm adhesion to collagen structures exposed at sites of vascular injury. Here, we determined the effects of specific activation of GPVI on the human platelet proteome by two-dimensional differential in-gel electrophoresis (2D-DIGE) and mass spectrometry. Methods and Results: Platelets from healthy human donors were isolated and purified. Platelets were stimulated with an activating monoclonal antibody specific for GPVI, or control IgG. Platelet proteins were subjected to 2D-DIGE with extensive software-assisted image analysis. Subsequent identification of the differentially abundant proteins was carried out by MALDI TOF/TOF MS and LC ESI-MS/MS. We identified 8 differentially regulated proteins associated with cell signaling, metabolism, organization and rearrangement of the cytoskeleton, and membrane trafficking. Differentially abundant proteins included pleckstrin, beta-centractin, src substrate cortactin, charged multivesicular body protein 3, aldose reductase and protein disulfide isomerase-associated 3 precursor. Conclusion: Specific platelet activation via GPVI results in the differential regulation of several proteins. The results provide further insight into the mechanisms that underlie platelet activation through the GPVI receptor, which may help to identify novel pharmacological targets.

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