Targeting VPS41 induces methuosis and inhibits autophagy in cancer cells. Issue 2 (16th February 2023)

• Record Type: Journal Article
• Authors: Liu, Yue; Sun, Yong; Xu, Yuliang; Dong, Ting; Qian, Lilin; Zheng, Hongbo; Gao, Yun; Chu, Zhaojun; Fu, Xiaojie; Zhang, Hanrui; Xie, Feng; Zhang, Chunyang; Tang, Yajie; Lou, Hongxiang
• Is Part Of: Cell chemical biology. Volume 30:Issue 2(2023)
• Page Start: 130
• Page End: 143.e5
• Publication Date: 2023-02-16
• Subjects: HOPS complex -- VPS41 -- methuosis -- micropinocytosis -- autophagy -- cytoplasmic vacuolization -- liverworts; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2023.01.002
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: The homotypic fusion and vacuole protein sorting (HOPS) complex mediates membrane trafficking involved in endocytosis, autophagy, lysosome biogenesis, and phagocytosis. Defects in HOPS subunits are associated with various forms of cancer, but their potential as drug targets has rarely been examined. Here, we identified vacuolar protein sorting-associated protein 41 homolog (VPS41), a subunit of the HOPS complex, as a target of methyl 2, 4-dihydroxy-3-(3-methyl-2-butenyl)-6-phenethylbenzoate (DMBP), a natural small molecule with preferable anticancer activity. DMBP induced methuosis and inhibited autophagic flux in cancer cells by inhibiting the function of VPS41, leading to the restrained fusion of late endosomes and autophagosomes with lysosomes. Moreover, DMBP effectively inhibited metastasis in a mouse metastatic melanoma model. Collectively, the current work revealed that targeting VPS41 would provide a valuable method of inhibiting cancer proliferation through methuosis. Graphical abstract: Highlights: Identification of VPS41 as a direct target of DMBP DMBP induces methuosis and inhibits autophagy in cancer cells DMBP inhibits the fusion of late endosomes and autophagosomes with lysosomes Abstract : Liu et al. report DMBP as a methuosis inducer that impedes the membrane fusion events. Further study identifies VPS41 as a potential target of DMBP, through which DMBP inhibits the fusion of late endosomes and autophagosomes with lysosomes.