Vicenistatin induces early endosome-derived vacuole formation in mammalian cells.
Homotypic fusion of early endosomes is important for efficient protein trafficking and sorting. The key controller of this process is Rab5 which regulates several effectors and PtdInsPs levels, but whose mechanisms are largely unknown. Here, we report that vicenistatin, a natural product, enhanced homotypic fusion of early endosomes and induced the formation of large vacuole-like structures in mammalian cells. Unlike YM201636, another early endosome vacuolating compound, vicenistatin did not inhibit PIKfyve activity in vitro but activated Rab5-PAS pathway in cells. Furthermore, vicenistatin increased the membrane surface fluidity of cholesterol-containing liposomes in vitro, and cholesterol deprivation from the plasma membrane stimulated vicenistatin-induced vacuolation in cells. These results suggest that vicenistatin is a novel compound that induces the formation of vacuole-like structures by activating Rab5-PAS pathway and increasing membrane fluidity.
a Graduate School of Life and Environmental Sciences , University of Tsukuba , Tsukuba , Japan.
Yuko
Y
Nishiyama
a Graduate School of Life and Environmental Sciences , University of Tsukuba , Tsukuba , Japan.
Tomohiro
T
Ohmichi
b Chemical Biology Research Group, RIKEN CSRS , Wako, Japan.
Sayaka
S
Kazami
a Graduate School of Life and Environmental Sciences , University of Tsukuba , Tsukuba , Japan.
Hiroki
H
Iwasaki
c Graduate School of Pharmaceutical Sciences , Tohoku University , Sendai , Japan.
Kousuke
K
Mano
a Graduate School of Life and Environmental Sciences , University of Tsukuba , Tsukuba , Japan.
Yoko
Y
Nagumo
d Graduate School of Science and Engineering , Tokyo Institute of Technology , Tokyo , Japan.
Fumitaka
F
Kudo
e Faculty of Life and Environmental Sciences , University of Tsukuba , Tsukuba , Japan.
Sosaku
S
Ichikawa
c Graduate School of Pharmaceutical Sciences , Tohoku University , Sendai , Japan.
Yoshiharu
Y
Iwabuchi
c Graduate School of Pharmaceutical Sciences , Tohoku University , Sendai , Japan.
Naoki
N
Kanoh
d Graduate School of Science and Engineering , Tokyo Institute of Technology , Tokyo , Japan.
Tadashi
T
Eguchi
b Chemical Biology Research Group, RIKEN CSRS , Wako, Japan.
Hiroyuki
H
Osada
e Faculty of Life and Environmental Sciences , University of Tsukuba , Tsukuba , Japan.
Takeo
T
Usui
D000617:Aminoglycosides / Q000494:pharmacology*; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D011992:Endosomes / Q000187:drug effects* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005420:Flavoproteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007769:Lactams / Q000494:pharmacology*; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology*; D008561:Membrane Fusion / Q000187:drug effects*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D015398:Signal Transduction; D022161:Transport Vesicles / Q000187:drug effects / Q000378:metabolism; D014617:Vacuoles / Q000187:drug effects* / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
D000617:Aminoglycosides; D000631:Aminopyridines; D000900:Anti-Bacterial Agents; D002784:Cholesterol; D005420:Flavoproteins; D006575:Heterocyclic Compounds, 3-Ring; D047908:Intracellular Signaling Peptides and Proteins; D007769:Lactams; D008081:Liposomes; D018942:Macrolides; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D010744:Phosphoric Monoester Hydrolases; D020696:rab5 GTP-Binding Proteins; C540576:6-amino-N-(3-(4-(4-morpholinyl)pyrido(3',2'-4,5)furo(3,2-d)pyrimidin-2-yl)phenyl)-3-pyridinecarboxamide; C494631:VAC14 protein, human; C082785:vicenistatin; C492139:PIKFYVE protein, human; C522215:FIG4 protein, human; C427755:RAB5C protein, human
Rab5-PAS pathway; early endosome; membrane fluidity; vacuolation; vicenistatin