Abstract
Autophagy is an intracellular pathway for bulk protein degradation and the removal of damaged organelles by lysosomes. Autophagy was previously thought to be unselective; however, studies have increasingly confirmed that autophagy-mediated protein degradation is highly regulated. Abnormal autophagic protein degradation has been associated with multiple human diseases such as cancer, neurological disability and cardiovascular disease; therefore, further elucidation of protein degradation by autophagy may be beneficial for protein-based clinical therapies. Macroautophagy and chaperone-mediated autophagy (CMA) can both participate in selective protein degradation in mammalian cells, but the process is quite different in each case. Here, we summarize the various types of macroautophagy and CMA involved in determining protein degradation. For this summary, we divide the autophagic protein degradation pathways into four categories: the post-translational modification dependent and independent CMA pathways and the ubiquitin dependent and independent macroautophagy pathways, and describe how some non-canonical pathways and modifications such as phosphorylation, acetylation and arginylation can influence protein degradation by the autophagy lysosome system (ALS). Finally, we comment on why autophagy can serve as either diagnostics or therapeutic targets in different human diseases.
Highlights
Autophagy is an evolutionarily conserved eukaryotic process that can be initiated in response to both external and intracellular factors, including amino acid starvation [1], growth factor withdrawal [2], endoplasmic reticulum (ER) stress [3], hypoxia [4], oxidative stress [5], pathogen infection [6], and organelle signaling [7, 8], which are beneficial to cell survival under adverse conditions
ATG12 is conjugated to a lysine residue in ATG5 via the ATG7-ATG10 cascade, forming an www.impactjournals.com/oncotarget oligomeric ATG12-ATG5-ATG16 complex that promotes the conjugation of the carboxy-terminal Gly residue of ATG8 to phosphatidylethanolamine (PE) via ATG3 and ATG7 [10, 12]
Autophagic degradation has been demonstrated to be selectively and precisely regulated. Details regarding this type of degradation pathway remain largely unknown
Summary
Autophagy is an evolutionarily conserved eukaryotic process that can be initiated in response to both external and intracellular factors, including amino acid starvation [1], growth factor withdrawal [2], endoplasmic reticulum (ER) stress [3], hypoxia [4], oxidative stress [5], pathogen infection [6], and organelle signaling [7, 8], which are beneficial to cell survival under adverse conditions. The ubiquitin proteasome system (UPS) and the autophagy-lysosome system (ALS) are alternative ways to categorize protein degradation based on the functions of the proteins being degraded. Recent studies have indicated that oxidative stress can activate the CMA pathway and that this potentiation occurs at least partially because oxidized proteins are more unfolded to facilitate translocation into the lysosomal lumen.
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