Autophagy

Abstract

Autophagy comprises several evolutionarily conserved mechanisms for uptake and transport of proteins and even cytoplasmic organelles to the lysosome for degradation. Although the importance of autophagy for cell homeostasis and survival has long been appreciated, our understanding of how autophagy is carried out at the molecular level has recently benefited from genetic studies that have revealed the functions of many of the participating proteins. The importance of autophagy for maintaining quality control on proteins and organelles is underscored by the fact that many diseases exhibit dysfunctional autophagic activities, for example neurodegenerative diseases. When cells undergoing stress leading to deoxyribonucleic acid damage, mitochondrial damage, and/or accumulation of damaged proteins are unable to induce a sufficient autophagic response, genetic instability ensues and such cells are prone to accumulate oncogenic mutations. Thus, autophagy is required for multiple roles in the prevention of human disease.

Key Concepts

  • Though a basal or constitutive level of autophagy is present in almost all cell types all the time for elimination of damaged proteins and even dysfunctional organelles, for example, mitochondria, autophagy can be strongly induced to compensate for nutritional imbalances or in response to stresses such as DNA damage.
  • Autophagy is carried out by a set of more than 30 proteins encoded by the Autophagy‐Related genes (ATGs), the functions of which have been dissected using genetic and biochemical approaches.
  • lncreasingly, it is becoming clear that proteins encoded by ATG genes carry out functions in cellular pathways independent of their roles in autophagy.
  • Autophagy is a process in which a cup‐shaped, double‐membrane phagophore develops from a region of or near modified endoplasmic reticulum and closes, either unselectively in bulk or selectively, around sequestered cytoplasmic cargos, finally fusing with a lysosome to deliver the contents for degradation.
  • Dysregulated autophagy contributes to many pathologic processes including cancer and neurodegenerative diseases.

Keywords: autophagy; ATG; Beclin 1; LC3; mTORC1; p62/SQSTM1; PI3K; ULK1/2

Figure 1. The pathway for major molecular steps in autophagy. Upon activation, a preautophagosomal structure on or near the ER (endoplasmic reticulum) is formed, generating the phagophore or isolation membrane in a stepwise process as different proteins associate and recruit other players. Whenever mTORC1 is inactivated, the initiation complex of ULK1/2, ATG13, ATG101 (here 101) and FIP200 associate and the kinase activity is activated at the nascent phagophore. Thereby, ATG14 is phosphorylated, recruiting the Beclin1 followed by the entire PI3K complex. The local production of PI 3‐P (shown as a cloud) recruits the phospholipid binding proteins (here only WIPI is shown) and initiates the ubiquitin‐like conjugation reactions that produce first ATG12‐ATG5–ATG16, which must associate first with the phagophore, before conjugation of LC3‐PE can occur. ATG12‐ATG5–ATG16 is present in small amounts very early, even before the PI3K is fully active. Note that the association of the PI3K complex and ATG12‐ATG5–ATG16 with the phagophore is transient, and also that LC3 on the cytoplasmic side of the mature autophagosome is also cleaved away from the membrane. P62 (here 62) associates with poly‐ubiquitinated protein aggregates, then binding LC3, allowing the phagophore to engulf other cytosolic elements and organelles, growing and finally closing, forming the autophagosome, which, in turn, fuses with endocytic vesicles forming the so‐called mature autophagosome or amphisome. Subsequently, it is transported centrally on microtubules by dynein, finally fusing with a lysosome. In the lysosome, the sequestered material is digested by lysosomal acid hydrolases (proteases and lipases).
Figure 2. Regulation of autophagy. The protein kinase complex, mTORC1, made up of the catalytic subunit, Target of Rapamycin (TOR), the Raptor regulatory/scaffold subunit and other proteins plays the central role in the signaling pathways involved in regulation of autophagy. The ULK1/2 kinase complex initiates autophagy when mTORC1 inactivation interrupts the inhibitory phosphorylation of ULK1/2. ULK1/2 phosphorylation targets include ATG13, FIP200 in the autophagy initiating complex, the ER‐associated protein ATG14 and Beclin 1. The latter recruit the remaining elements of the PI3K complex to the phagophore. This complex comprises the catalytic subunit Vps34, Vps15 and Beclin 1. However, Beclin1 availability is a major limitation, representing an important regulatory step, since it must be freed of its binding partners like to Bcl‐2 and Bcl‐XL, for example by Bcl‐2 phosphorylation (not shown). Thus, the requirement for Beclin 1 represents a cross‐talk between the core machineries regulating autophagy and apoptosis.
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Further Reading

Eisenberg‐Lerner A, Bialik S, Simon HU and Kimchi A (2009) Life and death partners: apoptosis, autophagy and the cross‐talk between them. Cell Death and Differentiation 16: 966–975.

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Yousefi S and Simon HU (2009) Autophagy in cells of the blood. Biochimica et Biophysica Acta 1793: 1461–1464.

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Simon, Hans‐Uwe, Friis, Robert, and Colombo, María I(Mar 2017) Autophagy. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021581.pub2]