Vacuolin-1 potently and reversibly inhibits autophagosome-lysosome fusion by activating RAB5A

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalNot applicablepeer-review

34 Scopus Citations
View graph of relations

Author(s)

  • Yingying Lu
  • Shichen Dong
  • Baixia Hao
  • Chang Li
  • Wenjing Guo
  • Qian Wang
  • King-Ho Cheung
  • Connie W.M. Wong
  • Wu-Tian Wu
  • Huss Markus

Related Research Unit(s)

Detail(s)

Original languageEnglish
Pages (from-to)1895-1905
Journal / PublicationAutophagy
Volume10
Issue number11
StatePublished - 1 Nov 2014

Link(s)

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.

Research Area(s)

  • Autophagosomes, Endosomes, Lysosomes, PH, RAB5A, Vacuolin-1

Citation Format(s)

Vacuolin-1 potently and reversibly inhibits autophagosome-lysosome fusion by activating RAB5A. / Lu, Yingying; Dong, Shichen; Hao, Baixia; Li, Chang; Zhu, Kaiyuan; Guo, Wenjing; Wang, Qian; Cheung, King-Ho; Wong, Connie W.M.; Wu, Wu-Tian; Markus, Huss; Yue, Jianbo.

In: Autophagy, Vol. 10, No. 11, 01.11.2014, p. 1895-1905.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalNot applicablepeer-review

Download Statistics

No data available