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Frey, L.* ; Ziętara, N.* ; Lyszkiewicz, M.* ; Marquardt, B.* ; Mizoguchi, Y.* ; Linder, M.I.* ; Liu, Y.* ; Giesert, F. ; Wurst, W. ; Dahlhoff, M.* ; Schneider, M.* ; Wolf, E.* ; Somech, R.* ; Klein, C.*

Mammalian VPS45 orchestrates trafficking through the endosomal system.

Blood 137, 1932-1944 (2021)
Postprint DOI PMC
Open Access Green
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 G-CSF receptor (G-CSFR) 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Endocytic Trafficking; Rabenosyn-5; Rab5; Transport; Proteins; Gene; Compartment; Biogenesis; Mutations; Effectors
Language english
Publication Year 2021
Prepublished in Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Journal Blood
Quellenangaben Volume: 137, Issue: 14, Pages: 1932-1944 Article Number: , Supplement: ,
Publisher American Society of Hematology
Publishing Place 2021 L St Nw, Suite 900, Washington, Dc 20036 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)
POF-Topic(s) 30204 - Cell Programming and Repair
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500500-001
Grants Deutsche Forschungsgemeinschaft (DFG) (Gottfried Wilhelm Leibniz Program)
Elite Network of Bavaria ("i-Target" doctoral program)
Deutsches Zentrum fur Infektionsforschung (DZIF)
Care-for-Rare Foundation
Bundesministerium fur Bildung und Forschung (BMBF) (German PID-NET)
Deutsche Forschungsgemeinschaft (DFG)
DOI 10.1182/blood.2020006871
WOS ID WOS:000646123500014
Scopus ID 85103766492
PubMed ID 33512427
Erfassungsdatum 2021-02-16
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