{"data":{"id":"10.6084/m9.figshare.c.2025398.v1","type":"dois","attributes":{"doi":"10.6084/m9.figshare.c.2025398.v1","prefix":"10.6084","suffix":"m9.figshare.c.2025398.v1","identifiers":[],"alternateIdentifiers":[],"creators":[{"name":"Lu, Yingying","givenName":"Yingying","familyName":"Lu","affiliation":[],"nameIdentifiers":[]},{"name":"Dong, Shichen","givenName":"Shichen","familyName":"Dong","affiliation":[],"nameIdentifiers":[]},{"name":"Hao, Baixia","givenName":"Baixia","familyName":"Hao","affiliation":[],"nameIdentifiers":[]},{"name":"Li, Chang","givenName":"Chang","familyName":"Li","affiliation":[],"nameIdentifiers":[]},{"name":"Zhu, Kaiyuan","givenName":"Kaiyuan","familyName":"Zhu","affiliation":[],"nameIdentifiers":[]},{"name":"Guo, Wenjing","givenName":"Wenjing","familyName":"Guo","affiliation":[],"nameIdentifiers":[]},{"name":"Wang, Qian","givenName":"Qian","familyName":"Wang","affiliation":[],"nameIdentifiers":[]},{"name":"Cheung, King-Ho","givenName":"King-Ho","familyName":"Cheung","affiliation":[],"nameIdentifiers":[]},{"name":"WM Wong, Connie","givenName":"Connie","familyName":"WM Wong","affiliation":[],"nameIdentifiers":[]},{"name":"Wu, Wu-Tian","givenName":"Wu-Tian","familyName":"Wu","affiliation":[],"nameIdentifiers":[]},{"name":"Markus, Huss","givenName":"Huss","familyName":"Markus","affiliation":[],"nameIdentifiers":[]},{"name":"Yue, Jianbo","givenName":"Jianbo","familyName":"Yue","affiliation":[],"nameIdentifiers":[]}],"titles":[{"title":"Vacuolin-1 potently and reversibly inhibits autophagosome-lysosome fusion by activating RAB5A"}],"publisher":"Taylor \u0026 Francis","container":{},"publicationYear":2015,"subjects":[{"subject":"Cancer"},{"subject":"Biological Sciences"},{"subject":"Immunology"},{"subject":"FOS: Clinical medicine","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"Chemistry"},{"subject":"Pharmacology"},{"subject":"Neuroscience"},{"subject":"Molecular Biology"},{"subject":"Genetics"},{"subject":"FOS: Biological sciences","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"Cell Biology"},{"subject":"Physics"},{"subject":"Biochemistry"}],"contributors":[],"dates":[{"date":"2015-12-05","dateType":"Created"},{"date":"2019-08-19","dateType":"Updated"},{"date":"2015","dateType":"Issued"}],"language":null,"types":{"ris":"GEN","bibtex":"misc","citeproc":"article","schemaOrg":"Collection","resourceType":"Collection","resourceTypeGeneral":"Collection"},"relatedIdentifiers":[{"relationType":"IsIdenticalTo","relatedIdentifier":"10.6084/m9.figshare.c.2025398","relatedIdentifierType":"DOI"}],"relatedItems":[],"sizes":[],"formats":[],"version":null,"rightsList":[{"rights":"Creative Commons Attribution 4.0 International","rightsUri":"https://creativecommons.org/licenses/by/4.0/legalcode","schemeUri":"https://spdx.org/licenses/","rightsIdentifier":"cc-by-4.0","rightsIdentifierScheme":"SPDX"}],"descriptions":[{"description":"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 Ca\u003csup\u003e2+\u003c/sup\u003e 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.","descriptionType":"Abstract"}],"geoLocations":[],"fundingReferences":[],"xml":"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