TY - JOUR
T1 - Mammalian VPS45 orchestrates trafficking through the endosomal system
AU - Frey, Laura
AU - Ziętara, Natalia
AU - Łyszkiewicz, Marcin
AU - Marquardt, Benjamin
AU - Mizoguchi, Yoko
AU - Linder, Monika I.
AU - Liu, Yanshan
AU - Giesert, Florian
AU - Wurst, Wolfgang
AU - Dahlhoff, Maik
AU - Schneider, Marlon R.
AU - Wolf, Eckhard
AU - Somech, Raz
AU - Klein, Christoph
N1 - Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/4/8
Y1 - 2021/4/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85103766492&partnerID=8YFLogxK
U2 - 10.1182/blood.2020006871
DO - 10.1182/blood.2020006871
M3 - Article
C2 - 33512427
AN - SCOPUS:85103766492
SN - 0006-4971
VL - 137
SP - 1932
EP - 1944
JO - Blood
JF - Blood
IS - 14
ER -