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000285035 041__ $$aEnglish
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000285035 1001_ $$00000-0002-5618-0755$$aGao, Jincheng$$b0
000285035 245__ $$aMutations in VPS18 lead to a neutrophil maturation defect associated with disturbed vesicle homeostasis.
000285035 260__ $$aLondon [u.a.]$$bNature Publishing Group$$c2026
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000285035 520__ $$aNeutrophils, the first cells to arrive at the site of inflammation, are rather short-lived cells and thus have to be constantly replenished. During neutrophil development, vesicle dynamics need to be fine-tuned and impaired vesicle trafficking has been linked to failure in neutrophil maturation. Here, we characterized the role of VPS18 as a central core component of CORVET & HOPS tethering complexes for neutrophil development. Using CRISPR/Cas9-engineered Hoxb8 cells with heterozygous mutations in Vps18, we found that VPS18 deficiency interfered with neutrophil development due to tethering complex instability. As a result, vesicle dynamics were impaired with a strong increase in LC3B-II and p62 levels, indicating autophagosome accumulation and reduced autophagic flux. With transmission electron microscopy, we verified the increase in autophagosomes and also found irregularly shaped vesicular structures in Vps18 mutants. Subsequently, Vps18 mutant neutrophil progenitors underwent premature apoptosis. We described a novel patient with a heterozygous stop-gain mutation in VPS18 suffering from neutropenia and recurrent infections. To verify our findings in the human system, we used human induced pluripotent stem cells (iPSCs). Upon differentiation into neutrophils, loss of VPS18 resulted in an almost complete absence of iPSC-derived developing neutrophils. Heterozygous VPS18 mutant and patient mutation-harboring iPSCs were characterized by strongly reduced numbers of developing neutrophils. Zebrafish larvae with heterozygous mutations in vps18 were also characterized by significantly reduced neutrophil numbers. This study shows the pivotal impact of VPS18 for adequate vesicle dynamics during neutrophil development which might be relevant in the context of vesicle trafficking during granulopoiesis and congenital neutropenia.
000285035 536__ $$0G:(DE-HGF)POF4-352$$a352 - Disease Mechanisms (POF4-352)$$cPOF4-352$$fPOF IV$$x0
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000285035 650_7 $$2NLM Chemicals$$aVesicular Transport Proteins
000285035 650_2 $$2MeSH$$aNeutrophils: metabolism
000285035 650_2 $$2MeSH$$aNeutrophils: pathology
000285035 650_2 $$2MeSH$$aAnimals
000285035 650_2 $$2MeSH$$aHumans
000285035 650_2 $$2MeSH$$aVesicular Transport Proteins: genetics
000285035 650_2 $$2MeSH$$aVesicular Transport Proteins: metabolism
000285035 650_2 $$2MeSH$$aZebrafish
000285035 650_2 $$2MeSH$$aMutation: genetics
000285035 650_2 $$2MeSH$$aHomeostasis
000285035 650_2 $$2MeSH$$aCell Differentiation
000285035 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000285035 650_2 $$2MeSH$$aAutophagy
000285035 650_2 $$2MeSH$$aCRISPR-Cas Systems
000285035 650_2 $$2MeSH$$aNeutropenia: genetics
000285035 650_2 $$2MeSH$$aNeutropenia: pathology
000285035 650_2 $$2MeSH$$aAutophagosomes: metabolism
000285035 650_2 $$2MeSH$$aMale
000285035 7001_ $$0P:(DE-2719)9001059$$aBader, Almke$$b1
000285035 7001_ $$aLinder, Monika I$$b2
000285035 7001_ $$aCheng, Jingyuan$$b3
000285035 7001_ $$00000-0002-3110-6137$$aRichter, Mathis$$b4
000285035 7001_ $$00000-0001-9666-8301$$ada Costa, Raul$$b5
000285035 7001_ $$aZehrer, Annette$$b6
000285035 7001_ $$00009-0006-0965-9903$$aMitt, Karl$$b7
000285035 7001_ $$aPopper, Bastian$$b8
000285035 7001_ $$00000-0003-1000-7989$$aMeissner, Felix$$b9
000285035 7001_ $$aWei, Xiang$$b10
000285035 7001_ $$ade Vega Gómez, Enrique$$b11
000285035 7001_ $$aTatematsu, Megumi$$b12
000285035 7001_ $$aRohlfs, Meino$$b13
000285035 7001_ $$00000-0001-8862-3752$$aFrenz-Wiessner, Stephanie$$b14
000285035 7001_ $$aKiziltug, Mehmet$$b15
000285035 7001_ $$aSomekh, Ido$$b16
000285035 7001_ $$aYacobovich, Joanne$$b17
000285035 7001_ $$aSteinberg-Shemer, Orna$$b18
000285035 7001_ $$aSomech, Raz$$b19
000285035 7001_ $$00000-0002-7854-0694$$aSoehnlein, Oliver$$b20
000285035 7001_ $$0P:(DE-2719)2241638$$aSchmid, Bettina$$b21$$udzne
000285035 7001_ $$aKlein, Christoph$$b22
000285035 7001_ $$00000-0001-7729-6565$$aWalzog, Barbara$$b23
000285035 7001_ $$00000-0001-8491-9820$$aMaier-Begandt, Daniela$$b24
000285035 773__ $$0PERI:(DE-600)2541626-1$$a10.1038/s41419-025-08338-w$$gVol. 17, no. 1, p. 180$$n1$$p180$$tCell death & disease$$v17$$x2041-4889$$y2026
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