The process of autophagy is highly conserved in all eukaryotic organisms and is enhanced by various intra- and extracellular stimuli. Autophagy is essential for cellular homeostasis, cellular protein and organelle quality control and disposal, and adaptation of the organism to environmental stress. (Levine and Kroemer, 2008; Mizushima and Komatsu, 2011). In autophagy initiation, the ULK1-serine-threonine kinase complex (involving ULK1, FIP200, ATG13, and ATG101) plays a major role by phosphorylating and thereby activating several downstream proteins. In higher eukaryotes, many autophagy genes have additionally functionally diversified to
- facilitate the transport of extracellular cargo to the lysosome
- promote plasma membrane localization or extracellular release of intracellular cargo
- coordinate intracellular communication with various cell signaling pathways.
These downstream functions are in the true sense, not autophagy. Accordingly, they are referred to as ATG gene-dependent pathways.
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The nuclear ATG proteins are necessary but not sufficient for intact degradative autophagy in human cells. Degradation of autophagosomal cargo can only occur via successful fusion of the autophagosome with a functional lysosome. Prerequisite for these essential processes are: on the one hand an intact lysosomal biogenesis
- an undisturbed autophagolysosomal fusion process per se (Yu et al. 2018)
- an unimpaired lysosomal (enzymatic) function (Shen and Mizushima, 2014)
- and ultimately a restoration of intact lysosomal function (Chen and Yu, 2017).
Mutations in genes required for autophagy and lysosomal function that regulate these processes lead to frequent lines of dysfunction in cellular metabolism and to entirely different, often severe, disease patterns.