DC Element | Wert | Sprache |
dc.contributor.author | Lu, Yingying | |
dc.contributor.author | Dong, Shichen | |
dc.contributor.author | Hao, Baixia | |
dc.contributor.author | Li, Chang | |
dc.contributor.author | Zhu, Kaiyuan | |
dc.contributor.author | Guo, Wenjing | |
dc.contributor.author | Wang, Qian | |
dc.contributor.author | Cheung, King-Ho | |
dc.contributor.author | Wong, Connie W. M. | |
dc.contributor.author | Wu, Wu-Tian | |
dc.contributor.author | Markus, Huss | |
dc.contributor.author | Yue, Jianbo | |
dc.date.accessioned | 2021-12-23T16:19:04Z | - |
dc.date.available | 2021-12-23T16:19:04Z | - |
dc.date.issued | 2014 | |
dc.identifier.issn | 15548627 | |
dc.identifier.uri | https://osnascholar.ub.uni-osnabrueck.de/handle/unios/12970 | - |
dc.description.abstract | Autophagy is a catabolic lysosomal degradation process essential for cellular homeostasis and cell survival. Dysfunctional autophagy has been associated with a wide range of human diseases, e.g., cancer and neurodegenerative diseases. A large number of small molecules that modulate autophagy have been widely used to dissect this process and some of them, e.g., chloroquine (CQ), might be ultimately applied to treat a variety of autophagy-associated human diseases. Here we found that vacuolin-1 potently and reversibly inhibited the fusion between autophagosomes and lysosomes in mammalian cells, thereby inducing the accumulation of autophagosomes. Interestingly, vacuolin-1 was less toxic but at least 10-fold more potent in inhibiting autophagy compared with CQ. Vacuolin-1 treatment also blocked the fusion between endosomes and lysosomes, resulting in a defect in general endosomal-lysosomal degradation. Treatment of cells with vacuolin-1 alkalinized lysosomal pH and decreased lysosomal Ca2+ content. Besides marginally inhibiting vacuolar ATPase activity, vacuolin-1 treatment markedly activated RAB5A GTPase activity. Expression of a dominant negative mutant of RAB5A or RAB5A knockdown significantly inhibited vacuolin-1-induced autophagosome-lysosome fusion blockage, whereas expression of a constitutive active form of RAB5A suppressed autophagosome-lysosome fusion. These data suggest that vacuolin-1 activates RAB5A to block autophagosome-lysosome fusion. Vacuolin-1 and its analogs present a novel class of drug that can potently and reversibly modulate autophagy. | |
dc.description.sponsorship | Research Grant Council (RGC)Hong Kong Research Grants Council [782709M, 785911M, 769912M, 785213M, 17126614M]; Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [SFB 944]; This work was supported by Research Grant Council (RGC) grants (782709M, 785911M, 769912M, 785213M, and 17126614M) to JY and the Deutsche Forschungsgemeinschaft (SFB 944) to HM. | |
dc.language.iso | en | |
dc.publisher | TAYLOR & FRANCIS INC | |
dc.relation.ispartof | AUTOPHAGY | |
dc.subject | autophagosomes | |
dc.subject | CELL | |
dc.subject | Cell Biology | |
dc.subject | DEGRADATION | |
dc.subject | ENDOSOMES | |
dc.subject | EXOCYTOSIS | |
dc.subject | GTPASE | |
dc.subject | HUNTINGTON-DISEASE | |
dc.subject | lysosomes | |
dc.subject | MATURATION | |
dc.subject | MEMBRANE | |
dc.subject | pH | |
dc.subject | PROTEIN | |
dc.subject | RAB5A | |
dc.subject | V-ATPASES | |
dc.subject | vacuolin-1 | |
dc.title | Vacuolin-1 potently and reversibly inhibits autophagosome-lysosome fusion by activating RAB5A | |
dc.type | journal article | |
dc.identifier.doi | 10.4161/auto.32200 | |
dc.identifier.isi | ISI:000348314200003 | |
dc.description.volume | 10 | |
dc.description.issue | 11 | |
dc.description.startpage | 1895 | |
dc.description.endpage | 1905 | |
dc.contributor.orcid | 0000-0001-6384-5447 | |
dc.contributor.orcid | 0000-0003-4579-0790 | |
dc.contributor.orcid | 0000-0002-5423-9522 | |
dc.contributor.orcid | 0000-0002-5648-3705 | |
dc.contributor.orcid | 0000-0002-1089-3901 | |
dc.contributor.researcherid | AAC-4588-2019 | |
dc.contributor.researcherid | R-3192-2017 | |
dc.contributor.researcherid | K-8002-2015 | |
dc.identifier.eissn | 15548635 | |
dc.publisher.place | 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA | |
dcterms.isPartOf.abbreviation | Autophagy | |
dcterms.oaStatus | Bronze, Green Submitted, Green Published | |