Schematic overview of the autophagy process and genetic and drug targets to inhibit specific aspects of autophagy

Schematic overview of the autophagy process and genetic and drug targets to inhibit specific aspects of autophagy. Macroautophagy involves four main steps: induction, nucleation, elongation, and fusion/completion. Upon inhibition of mTORC1 by PI3K/AKT, the autophagy process is initiated, for example, when cells undergo starvation. The autophagy process then begins with the formation of a double-membrane structure, the phagophore, which elongates and matures into an autophagosome, sequestering the cytoplasmic cargo. The autophagosome fuses with lysosomes, generating autolysosomes, and the engulfed content is degraded through proteases, and macromolecules are released into the cytosol. Various, indicated ATG proteins and complexes facilitate certain steps in this catabolic pathway. In addition, the conversion of LC3-I to LC3-II, as well as the degradation of p62, together with the enclosed cargo, serve as markers of active autophagy in molecular and immunochemical assays. Chloroquine and other lysosomal compounds, as well as newly developed inhibitors and genetic targets to specifically block the autophagy pathway at certain points, are indicated. ROS = Reactive oxygen species; PI3K = Phosphoinositide3-kinase; AKT = Protein kinase B; mTORC1 = mammalian target of rapamycin complex I; ATG = Autophagy-related gene; ULK = Unc-51-like autophagy activating kinase; FIP200 = FAK family-interacting protein of 200 kDa; PiP3 = Phosphatidylinositol(3,4,5)-trisphosphate; VPS34 = Class III PI3K vacuolar protein sorting 34. Solid black and green arrows indicate activation and direction of autophagy steps; red dotted lines show inhibition; dotted green arrow indicates recycling of LC3-II-PE by ATG4s.

Publication

Current Outlook on Autophagy in Human Leukemia: Foe in Cancer Stem Cells and Drug Resistance, Friend in New Therapeutic Interventions. (2019) Katharina Rothe, et al. Int J Mol Sci. 2019 Feb;20(3):461. Figure: F1. All organisms Homo sapiens Mus musculus Drosophila melanogaster

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