Structure of the endosomal CORVET tethering complex

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 19, 2024

Abstract Cells depend on their endolysosomal system for nutrient uptake and downregulation of plasma membrane proteins. These processes rely endosomal maturation, which requires multiple fusion steps. Early endosome is promoted by the Rab5 GTPase its effector, hexameric CORVET tethering complex, homologous to lysosomal HOPS. How these related complexes recognize specific target membranes remains entirely elusive. Here, we solve structure cryo-electron microscopy revealed minimal requirements tethering. As expected, core HOPS resembles each other. However, function-defining subunits show marked structural differences. Notably, discover that unlike HOPS, depends not only but also phosphatidylinositol-3-phosphate (PI3P) lipid packing defects tethering, implying an organelle-specific code enables fusion. Our data suggest both shape interactions are conserved in metazoans, thus providing a paradigm how function.

Language: Английский

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The multiple facets of Rab proteins modulating the cellular distribution of cholesterol from the late endosomal compartment

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Journal Year: 2025, Volume and Issue: 1872(3), P. 119896 - 119896

Published: Jan. 7, 2025

Language: Английский

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Improved CAR internalization and recycling through transmembrane domain optimization reduces CAR-T cytokine release and exhaustion

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 27, 2025

Background Anti-CD19 chimeric antigen receptor T (CAR-T) cell therapy has proven effective for treating relapsed or refractory acute B leukemia. However, challenges such as cytokine release syndrome, dysfunction, and exhaustion persist. Enhancing CAR-T efficacy through changing CAR internalization recycling is a promising approach. The transmembrane domain the easiest motif to optimize modulating without introducing additional domains, its impact on not yet been thoroughly explored. In this study, we aim enhance function by focusing solely design. Methods Utilizing plasmid construction lentivirus generation, get two different cells [19CAR-T(1a) 19CAR-T(8α)]. Through co-culture with tumor cells, evaluate dynamic change, activation levels, markers, mitochondrial function, differentiation in both cells. Furthermore, immunofluorescence microscopy analysis performed reveal localization of internalized molecules. RNA sequencing used detect transcriptome activated Finally, mouse study utilized verify anti-tumor 19CAR-T(1a) vivo . Results Our findings demonstrate that lower surface expression, faster internalization, higher rate compared 19CAR-T(8α). Internalized 19CAR(1a) co-localizes more early endosomes, less lysosomes than 19CAR(8α). These features result release, reduced markers 19CAR-T(1a). CD1a also exhibit superior ability Conclusion Overall, plays critical role function. An optimized can alleviate syndrome reduce exhaustion, providing direction design

Language: Английский

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Unraveling the adaptive evolution and functional diversification of Rab GTPases in Salix matsudana under salt condition

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: 310, P. 143615 - 143615

Published: April 28, 2025

Language: Английский

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Lytic photoreceptor cell death caused by Rab escort protein deficiency in Drosophila

FEBS Letters, Journal Year: 2025, Volume and Issue: unknown

Published: May 5, 2025

Choroideremia (CHM) is a rare X‐linked recessive form of inherited retinal degeneration caused by the deficiency Rab escort protein 1 (REP1)‐encoding CHM gene. REP1 essential for post‐translational prenylation key players in intracellular membrane trafficking, GTPases. In this study, we aimed to analyze mechanisms Rep using Drosophila retina as model system. GTPases lost their association ability and diffused into cytoplasm, accumulation unprenylated Rab6 Rab7 was observed Rep‐deficient photoreceptors. Notably, photoreceptors underwent progressive cell death via swelling rupture rather than apoptosis. These findings provide new insight seek therapeutic approach CHM. Impact statement an (Rep‐1). We used study mechanism Rep‐deficiency found that undergo

Language: Английский

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The Underlying Rab Network of MRGPRX2-Stimulated Secretion Unveils the Impact of Receptor Trafficking on Secretory Granule Biogenesis and Secretion

Cells, Journal Year: 2024, Volume and Issue: 13(1), P. 93 - 93

Published: Jan. 1, 2024

MRGPRX2, the human member of MAS-related G-protein-coupled receptors (GPCRs), mediates immunoglobulin E (IgE)-independent responses a subset mast cells (MCs) that are associated with itch, pain, neurogenic inflammation, and pseudoallergy to drugs. The mechanisms underlying MRGPRX2 its multiple diverse ligands still not completely understood. Given close association between GPCR location function, key role played by Rab GTPases in controlling discrete steps along vesicular trafficking, we aimed reveal pathways directly impact MRGPRX2-mediated exocytosis identifying Rabs influence this process. For purpose, screened 43 for their functional phenotypic impacts on MC degranulation response synthetic ligand compound 48/80 (c48/80), which is often used as gold standard ligands, or substance P (SP), an important trigger neuroinflammatory responses. Results study highlight roles macropinocytosis autophagy exocytosis, demonstrating feedback control internalization post-endocytic trafficking triggered exocytosis.

Language: Английский

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RPGR is a guanine nucleotide exchange factor for the small GTPase RAB37 required for retinal function via autophagy regulation

Cell Reports, Journal Year: 2024, Volume and Issue: 43(4), P. 114010 - 114010

Published: March 26, 2024

Although the small GTPase RAB37 acts as an organizer of autophagosome biogenesis, upstream regulatory mechanism autophagy via guanosine diphosphate (GDP)-guanosine triphosphate (GTP) exchange in maintaining retinal function has not been determined. We found that retinitis pigmentosa regulator (RPGR) is a guanine nucleotide factor activates by accelerating GDP-to-GTP exchange. RPGR directly interacts with RPGR-RCC1-like domain to promote through stimulating Rpgr knockout (KO) mice leads photoreceptor degeneration owing impairment retina. Notably, retinopathy phenotypes KO retinas are rescued adeno-associated virus-mediated transfer pre-trans-splicing molecules, which produce normal mRNAs trans-splicing retinas. This rescue upregulates re-expression accelerate exchange; thus, homeostasis reverts normal. Taken together, these findings provide important missing link for coordinating GDP-GTP and regulation.

Language: Английский

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RAB42 overexpression correlates with poor prognosis, immune cell infiltration and chemoresistance

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: July 19, 2024

Background RAB42 (Ras-related protein 42) is a new small GTPase that controls the vesicular trafficking from endosomes to trans-Golgi network in mammalian cells. However, role of multiple cancers, especially liver hepatocellular carcinoma (LIHC), has not been well investigated. Methods A variety cancer-related databases and online tools, including TCGA, GTEx, TARGET, QUANTISEQ, EPIC, RNAactDrug, CTR-DB, TIMER algorithms Sangerbox, were applied explore correlation expression with prognosis, immune microenvironment, regulatory network, RNA modification, pathway activation drug sensitivity pan-cancer. The prognostic, immunomodulatory tumor-promoting effects verified various malignancies determined by series vitro cellular experiments. Results significantly overexpressed most cancers advanced pathological stages. Its overexpression correlated poor survival high diagnostic accuracy (AUC > 0.80). only correlates distinct stromal infiltration level checkpoint molecules, but also associates weak cell infiltration, genes expression, immunotherapeutic response inhibitors (ICIs). Additionally, enhanced m6A methylation-related (MRGs) its interactors. Moreover, serves as drug-resistant marker certain chemotherapies acts potential biomarker for LIHC. Notably, or promotes proliferation, migration invasion Conclusion Overexpressed prognostic therapeutic target pan-cancer,

Language: Английский

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Mast Cells and Mas-related G Protein-coupled Receptor X2: Itching for Novel Pathophysiological Insights to Clinical Relevance

Current Allergy and Asthma Reports, Journal Year: 2024, Volume and Issue: 25(1)

Published: Nov. 25, 2024

Abstract Purpose of Review Clinical interest in non-IgE activation mast cells has been growing since the description human MRGPRX2 receptor. Its participation many allergic and inflammatory conditions such as non histaminergic itch, urticaria, asthma drug hypersensitivity growing. We present here an updated review its structure, expression biology to help understand diseases attributed and/or overpexression search for agonists antagonists clinical utility. Recent Findings The patients presenting anaphylaxis when exposed one or multiple general anesthetics, antibiotics, opiods other agents provided evidence potential heterogeneity humans. Summary This provides most recent developments into receptor tissue signaling pathways including enhancement IgE-mediated cell activation. New insight is described future adress modulations.

Language: Английский

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CRISPR/CasRx-Mediated Knockdown of Rab7B Restores Incomplete Cell Shape Induced by Pelizaeus-Merzbacher Disease-Associated PLP1 p.Ala243Val

Neuroscience Insights, Journal Year: 2024, Volume and Issue: 19

Published: Jan. 1, 2024

Pelizaeus-Merzbacher disease (PMD, currently known as hypomyelinating leukodystrophy type 1 [HLD1]) is a hereditary and/or demyelinating associated with the proteolipid protein (plp1) gene in central nervous system (CNS). One of major causes this condition incomplete or defective oligodendroglial cell myelin sheath formation triggered by endoplasmic reticulum (ER) stress and subsequent unfolded response (UPR). The HLD1-associated Ala-243-to-Val mutation (p.Ala243Val) PLP1 widely recognized to trigger morphological differentiation, primarily due ER stress. We have previously reported that knockdown Rab7B (also Rab42), small GTP/GDP-binding involved intracellular vesicle trafficking around lysosome, can recover chemical stress-induced shapes FBD-102b line, model differentiation. Here, we present findings indicating induced p.Ala243Val be restored using clustered regularly interspaced short palindromic repeats (CRISPR) CasRx Cas13d) system. Also, promoted lysosome-associated membrane (LAMP1)-positive organelles. These results highlight unique role modulating changes potentially facilitating transport mutated LAMP1-positive organelles, suggesting its potential therapeutic target for alleviating HLD1 phenotypes, at least part, molecular cellular levels.

Language: Английский

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