TY  - JOUR
AU  - Gao, Jincheng
AU  - Bader, Almke
AU  - Linder, Monika I
AU  - Cheng, Jingyuan
AU  - Richter, Mathis
AU  - da Costa, Raul
AU  - Zehrer, Annette
AU  - Mitt, Karl
AU  - Popper, Bastian
AU  - Meissner, Felix
AU  - Wei, Xiang
AU  - de Vega Gómez, Enrique
AU  - Tatematsu, Megumi
AU  - Rohlfs, Meino
AU  - Frenz-Wiessner, Stephanie
AU  - Kiziltug, Mehmet
AU  - Somekh, Ido
AU  - Yacobovich, Joanne
AU  - Steinberg-Shemer, Orna
AU  - Somech, Raz
AU  - Soehnlein, Oliver
AU  - Schmid, Bettina
AU  - Klein, Christoph
AU  - Walzog, Barbara
AU  - Maier-Begandt, Daniela
TI  - Mutations in VPS18 lead to a neutrophil maturation defect associated with disturbed vesicle homeostasis.
JO  - Cell death & disease
VL  - 17
IS  - 1
SN  - 2041-4889
CY  - London [u.a.]
PB  - Nature Publishing Group
M1  - DZNE-2026-00160
SP  - 180
PY  - 2026
AB  - Neutrophils, 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 </td><td width="150">
AB  -  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.
KW  - Neutrophils: metabolism
KW  - Neutrophils: pathology
KW  - Animals
KW  - Humans
KW  - Vesicular Transport Proteins: genetics
KW  - Vesicular Transport Proteins: metabolism
KW  - Zebrafish
KW  - Mutation: genetics
KW  - Homeostasis
KW  - Cell Differentiation
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - Autophagy
KW  - CRISPR-Cas Systems
KW  - Neutropenia: genetics
KW  - Neutropenia: pathology
KW  - Autophagosomes: metabolism
KW  - Male
KW  - Vesicular Transport Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41526335
DO  - DOI:10.1038/s41419-025-08338-w
UR  - https://pub.dzne.de/record/285035
ER  -