Department of Pediatrics, Dr von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.
Blood. 2021 Apr 8;137(14):1932-1944. doi: 10.1182/blood.2020006871.
Vacuolar protein sorting 45 homolog (VPS45), a member of the Sec1/Munc18 (SM) family, has been implicated in the regulation of endosomal trafficking. VPS45 deficiency in human patients results in congenital neutropenia, bone marrow fibrosis, and extramedullary renal hematopoiesis. Detailed mechanisms of the VPS45 function are unknown. Here, we show an essential role of mammalian VPS45 in maintaining the intracellular organization of endolysosomal vesicles and promoting recycling of cell-surface receptors. Loss of VPS45 causes defective Rab5-to-Rab7 conversion resulting in trapping of cargos in early endosomes and impaired delivery to lysosomes. In this context, we demonstrate aberrant trafficking of the granulocyte colony-stimulating factor receptor in the absence of VPS45. Furthermore, we find that lack of VPS45 in mice is not compatible with embryonic development. Thus, we identify mammalian VPS45 as a critical regulator of trafficking through the endosomal system and early embryogenesis of mice.
液泡分选蛋白 45 同源物（VPS45）是 Sec1/Munc18（SM）家族的成员，它参与了内体运输的调节。人类患者中 VPS45 的缺乏会导致先天性中性粒细胞减少症、骨髓纤维化和骨髓外肾造血。VPS45 功能的详细机制尚不清楚。在这里，我们显示了哺乳动物 VPS45 在维持内溶酶体囊泡的细胞内组织和促进细胞表面受体的再循环方面的重要作用。VPS45 的缺失会导致 Rab5 到 Rab7 的转换缺陷，从而导致早期内体中的货物捕获，并损害向溶酶体的输送。在这种情况下，我们证明了 VPS45 缺失会导致粒细胞集落刺激因子受体的异常运输。此外，我们发现 VPS45 在小鼠中的缺乏与胚胎发育不相容。因此，我们确定哺乳动物 VPS45 是内体系统运输和小鼠早期胚胎发生的关键调节因子。
