Autophagy

María Isabel Colombo, IHEM‐CONICET‐ Facultad de Ciencias Médicas‐ Universidad Nacional de Cuyo, Mendoza, Argentina
Hans‐Uwe Simon, Institute of Pharmacology, Bern, Switzerland

Published online: December 2009

DOI: 10.1002/9780470015902.a0021581

Autophagy is a conserved proteolytic mechanism that degrades cytoplasmic material including cell organelles. Although the importance of autophagy for cell homeostasis and survival has long been appreciated, our understanding of how autophagy is regulated at a molecular level just recently evolved. The importance of autophagy for the quality control of proteins is underscored by the fact that many neurodegenerative and myodegenerative diseases are characterized by an increased but still insufficient autophagic activity. Similarly, if the cellular stress, leading to deoxyribonucleic acid (DNA) damage, mitochondrial damage and/or damaged proteins, does not result in sufficient autophagic repair mechanisms, cells seem to be prone to transform into tumour cells. Therefore, autophagy has multiple roles to play in the causation and prevention of human diseases.

Key concepts:

  • Autophagy is a cellular stress response induced to ensure cell survival, but excess autophagy may lead to cell death.
  • The kinases TOR (target of rapamycin) and PI3K (phosphatidyl inositol 3 kinase) are two essential components of the autophagy molecular machinery.
  • The family of genes or proteins called Atg (for autophagy related) comprises the core of the molecular machinery of autophagy.
  • Upon autophagy induction the enwrapped cytoplasmic components and organelles are recycled by degradation in the autolysosome.
  • Autophagy can be dysregulated and may contribute to many pathologic processes.

Keywords: autophagy; cell death; diseases; kinases; LC3

Figure 1. Major molecular components of the autophagy pathway. On activation a pre-autophagosomal structure is initially formed generating the phagophore or isolation membrane, which engulfs organelles and other cytoplasmic components. This structure growths and closes, forming the autophagosome, which, in turn, fuses with endocytic vesicles forming the so-called amphisome. Finally, fusion with the lysosomes takes place and the sequestered material is digested by the lysosomal enzymes. Key components of the molecular machinery involved in each step of the autophagy are depicted. Inset: the two ubiquitin-like conjugation systems that lead to the binding of LC3 to the autophagosomal membrane.
Figure 2. Regulation of autophagy. The PI3K class III and the protein kinase TOR play central roles in the signalling pathways involved in nutrient regulation of autophagy. The complex PI3K class III (Vps34)/Beclin 1 positively regulates autophagy whereas TOR inhibits this pathway. Binding of the antiapoptotic protein Bcl-2 to Beclin 1 decreases the capacity of Beclin 1 to activate autophagy. Starvation-dependent induction of autophagy stimulates the dissociation of Bcl-2 and Beclin 1. The crosstalk between the core machineries regulating autophagy and apoptosis is depicted.
Figure 3. The potential role of defective autophagy in tumour development. Autophagy acts in tumour suppression by removing damaged organelles and proteins, and reduces genetic instability. It may also cooperate with apoptosis to kill damaged cells. Moreover, some autophagic genes have an inhibitory effect on cell proliferation.
Figure 4. Autophagy acts as a cytoprotective mechanism in anticancer therapy leading to drug resistance. The specific reduction of autophagic activity in cancer cells might be beneficial under these circumstances.
Figure 5. Three escape mechanisms of pathogens on phagocytosis and the role of autophagy. (1) Escape from phagosomes into the cytosol (e.g. Listeria monocytogeneses). (2) Prevention of fusion with lysosome (e.g. Salmonella enterica). Similarly, prevention of acidification has also been observed (e.g. Mycobacterium tuberculosis). (3) Pathogens in the cytosol can be trapped by autophagosomes and degraded via the autophagic machinery. However, some pathogens can also escape from this degradation system by preventing the fusion between autophagosomes and lysosomes (e.g. Legionella pneumophila).
Figure 6. Schematic representation of the crosstalk between autophagy and apoptosis. (1) Following a death trigger the cell undergoes rapid apoptosis without induction of autophagy. (2) The death trigger induces autophagy, which is a prerequisite for apoptosis induction (2.1.). If apoptosis is blocked, the cell may undergo autophagic cell death (2.2.). Finally, the damage induced by the death trigger might be repaired and the cell survives due to autophagy (2.3.).
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Related Sub-Topics:

Intracellular and Extracellular Signalling | Cell Death and Cellular Senescence | Molecular Genetics of Common and Complex Disease | Mechanisms of Cell Death, Senescence and Metabolism
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Article Title: Autophagy
 
How to Cite close
Isabel Colombo, María, and Simon, Hans‐Uwe(Dec 2009) Autophagy. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021581]