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@ARTICLE{Gao:285035,
      author       = {Gao, Jincheng and Bader, Almke and Linder, Monika I and
                      Cheng, Jingyuan and Richter, Mathis and da Costa, Raul and
                      Zehrer, Annette and Mitt, Karl and Popper, Bastian and
                      Meissner, Felix and Wei, Xiang and de Vega Gómez, Enrique
                      and Tatematsu, Megumi and Rohlfs, Meino and Frenz-Wiessner,
                      Stephanie and Kiziltug, Mehmet and Somekh, Ido and
                      Yacobovich, Joanne and Steinberg-Shemer, Orna and Somech,
                      Raz and Soehnlein, Oliver and Schmid, Bettina and Klein,
                      Christoph and Walzog, Barbara and Maier-Begandt, Daniela},
      title        = {{M}utations in {VPS}18 lead to a neutrophil maturation
                      defect associated with disturbed vesicle homeostasis.},
      journal      = {Cell death $\&$ disease},
      volume       = {17},
      number       = {1},
      issn         = {2041-4889},
      address      = {London [u.a.]},
      publisher    = {Nature Publishing Group},
      reportid     = {DZNE-2026-00160},
      pages        = {180},
      year         = {2026},
      abstract     = {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 $\&$ 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.},
      keywords     = {Neutrophils: metabolism / Neutrophils: pathology / Animals
                      / Humans / Vesicular Transport Proteins: genetics /
                      Vesicular Transport Proteins: metabolism / Zebrafish /
                      Mutation: genetics / Homeostasis / Cell Differentiation /
                      Induced Pluripotent Stem Cells: metabolism / Autophagy /
                      CRISPR-Cas Systems / Neutropenia: genetics / Neutropenia:
                      pathology / Autophagosomes: metabolism / Male / Vesicular
                      Transport Proteins (NLM Chemicals)},
      cin          = {AG Schmid München},
      ddc          = {570},
      cid          = {I:(DE-2719)1140002},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41526335},
      doi          = {10.1038/s41419-025-08338-w},
      url          = {https://pub.dzne.de/record/285035},
}