期刊
AUTOPHAGY
卷 16, 期 8, 页码 1547-1549出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2020.1786268
关键词
ATG14; autophagy; BECN1; inhibitor; protein-protein interaction
类别
资金
- University of Illinois at Chicago Department of Chemistry, College of Liberal Arts and Sciences
- National Center for Advancing Translational Sciences [UL1TR002003]
- UIC CCTS [NIH UL1TR002003]
- UICentre (drug discovery @ UIC) [2017-16]
The PIK3C3/VPS34-containing phosphatidylinositol 3-kinase (PtdIns3K) initiation complex (complex I) is necessary for macroautophagy/autophagy initiation and is comprised of PIK3R4/VPS15-PIK3C3/VPS34-BECN1-ATG14, while the endosomal trafficking complex (complex II) is necessary for vesicle trafficking and is comprised of PIK3R4/VPS15-PIK3C3/VPS34-BECN1-UVRAG. This composition difference was exploited to identify novel and specific autophagy inhibitors that disrupted the BECN1-ATG14 protein-protein interaction, without affecting vesicle trafficking. A cellular NanoBRET assay was implemented to identify these inhibitors, and one compound was able to successfully disrupt the BECN1-ATG14 interaction and inhibit autophagy, with limited impact on vesicle trafficking. These results reveal the first protein-protein interaction inhibitor targeting the autophagy initiation machinery and demonstrate the viability of targeting protein-protein interactions for the discovery of autophagy-specific modulators.
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