Function and Mechanisms of Autophagy

Autophagy is a cellular process performed by cells for degradation and recycling. The word autophagy refers to ‘self-eating’, thus implying the digestion occurring inside lysosomes. After digestion, the degradation products are translocated to the cytoplasm, where they are then used in the maintenance of cellular homeostasis. Regulated by the ATG proteins, autophagy is conserved from yeast to humans. In effect, it is a cellular response to starvation and stress, with its dysregulation being implicated in many pathological situations, ranging from infection to cancer and neurodegeneration.

Types of Autophagy

There are three main types of autophagy in mammalian cells: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Each of these pathways converges in lysosomes to ensure intracellular degradation. Macroautophagy is responsible for facilitating the recycling of cellular components, including organelles, by forming an autophagosome. In contrast, during microautophagy, proteins translocate directly into the lysosomes.

Finally, in the case of chaperone-mediated autophagy, the degradation of proteins is enabled, harboring a protein sequence particularly recognized by chaperones (e.g. Hsc70). Further, the recognition of the lysosomal membrane protein Lamp2A by Hsc70 can facilitate the unfolding and translocation of this protein inside the lysosomal lumen, which is where the degradation then occurs.

Figure 1

Physiology and Pathology

In cells and tissues, autophagy plays many essential roles. For instance, basal autophagy plays a vital role in the prevention of the accumulation of damaged proteins and organelles; reducing ER stress; and limiting the production of reactive oxygen species (ROS).

Conversely, induced autophagy is essential because it provides nutrients and building blocks during times of starvation. Thus, autophagy is essential during the development and differentiation of many cell types and in maintaining tissue homeostasis.

Autophagy also plays an essential role in the case of immunity, since it participates in the thymic selection and antigen presentation. Autophagy is also important for the maintenance of cellular homeostasis during aging. Thus, given these essential physiological roles, it is unsurprising that autophagy dysregulation has profound implications, especially in the pathology of a number of diseases.

Lapses or defects in autophagy have been linked to a variety of neurodegenerative diseases, which include proteinopathies and lysosomal storage diseases. Moreover, autophagy defects have also been reported in liver and muscle diseases. Defective autophagy has also been associated with other pathological diseases, such as diabetes and obesity, as well as inflammatory pathologies such as Crohn’s disease.

Figure 2

The Molecular Machinery Implicated in Macroautophagy

In mammals, during the primary stages of autophagy, two macromolecular complexes are formed: Class III PI 3-K complex and Atg1/ULK1 complex.

During autophagosome formation, other regulators, including Atg2A/B, WIPI 1/2, DFCP1, and VMP1, cooperate, along with the catalyzation of two conjugation reactions by Atg7. First, Atg5 and Atg12 – which are conjugated and bind to Atg16. Secondly, LC3 is cleaved by the protease Atg4 and binds to the lipid phosphatidylethanolamine (PE), which thereby facilitates its anchoring at the autophagosomal membrane. Once this is formed, the autophagosome then fuses with lysosomes or endosomes in a process involving several lysosomal proteins such as Lamp1 and Rab7.

Finally, after being degraded by the action of lysosomal hydrolases, the final products – including amino acids, lipids, and nucleotides – translocate to the cytoplasm via permeases, such as Atg22 (in yeast), present in the lysosomal membrane. These are then recycled for new anabolic reactions to sustain cell homeostasis.

Figure 3

Selective Autophagy

Autophagy specifically targets subcellular structures for lysosomal degradation. The processes are named differently, depending on the cargo: mitophagy for the specific elimination of mitochondria; ribophagy for ribosomes; and lipophagy for the degradation of lipid droplets.  

Pexophagy degrades peroxisomes and aggrephagy degrades intracellular protein aggregates and misfolded proteins such as those observed in many neurodegenerative conditions. In addition, xenophagy denotes the degradation of intracellular pathogens such as viruses and intracellular bacteria. Finally, it is important to note that other cellular components – like the endoplasmic reticulum (ER), micronuclei, glycogen, and transposons – can also be specifically targeted by autophagosomes for degradation.

Figure 4

Further Reading

  • Kroemer et al (2010) Autophagy and the integrated stress response. Mol.Cell 40 280.
  • Yang and Klionsky (2010) Eaten alive: a history of macroautophagy. Nat.Cell Biol. 12 814.
  • Mathew and White (2011) Autophagy in tumorigenesis and energy metabolism: friend by day, foe by night. Curr.Opin.Genet.Dev. 21 113.
  • Mizushima et al (2011) The role of atg proteins in autophagosome formation. Annu.Rev.Cell Dev.Biol. 27 107.

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Last updated: Jun 2, 2020 at 9:01 AM

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