Resources

Autophagy

Autophagy is an essential catabolic pathway by which cytoplasmic materials are delivered to and degraded in the lysosome. This highly regulated pathway is physiologically essential, ensuring nutrient recycling, and cellular and organismal homeostasis during stress. It is activated by various endogenous and exogenous stimuli. In particular, autophagy is required to allow sessile organisms to cope with biotic or abiotic stress conditions. It is thought that these various environmental signaling pathways are somehow integrated with autophagy signaling. Inasmuch as faulty autophagy has been associated with aging, neuronal degeneration disorders, diabetes, and fatty liver, autophagy is regarded as a potential therapeutic target.

Forms of Cell Autophagy

Autophagy is an evolutionary conserved catabolic process used by eukaryotic cells for the degradation of damaged or superfluous proteins and organelles. There are roughly three main forms of autophagy:

  • Macro-autophagy is the major type of autophagy. It involves the sequestering of cellular constituents in double-membrane vesicles (autophagosomes) and subsequent delivery to lysosomes for degradation. It can be nonselective or selective. Nonselective autophagy is used for the turnover of bulk cytoplasm under starvation conditions. Selective autophagy targets damaged or superfluous mitochondria (mitophagy), peroxisomes (pexophagy), lipid droplets (lipophagy) and microbes (xenophagy).
  • Micro-autophagy is the second type of autophagy. The lysosome itself engulfs small components of the cytoplasm by inward invagination of the lysosomal membrane.
  • Chaperone-mediated autophagy does not involve membrane reorganization, instead, substrate proteins directly translocate across the lysosomal membrane during chaperone-mediated autophagy.

Process and Regulation of Cell Autophagy

Autophagy is mainly regulated by nutrients, growth factors and stress. It begins with the formation of the ‘‘isolation membrane’’ also known as phagophore which then extends and closes to become autophagosomes. Subsequently, autophagosomes mature by fusing with late endosomes and lysosomes, thereby forming autolysosomes.

In mammalian cells, Protein kinase B (PKB, also known as Akt), mitogen-activated protein kinase (MAKP)-Erk, p53, and adenosine 5’ adenosine monophosphate-activated protein kinase (AMPK) pathways participate in the expression of autophagy-related genes (Atgs). Autophagy is controlled by the orchestration of more than 30 Atgs whose expression is induced by FoxO. FoxO1 tends to induce Atg12 expression and FoxO3 priors to activating Lc3 genes. It has been reported that JNK is an effective negatively regulator of FoxO-dependent autophagy in neurons. The anti-apoptotic protein Bcl2 and other Bcl family members can inhibit autophagy.

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that belongs to the phosphatidylinositol kinase-related kinase (PIKK) family. It was first described as the physiological target of the immunosuppressant drug rapamycin. Subsequent studies established its role in protein translation and cell growth. Owing to its energy sensing functions, mTOR is considered as the master regulator of autophagy. The mTOR kinase is activated downstream of Akt kinase, MAKP-Erk and growth factor receptor, signaling when nutrients are available and acting to promote growth through induction of ribosomal protein expression and increased protein translation. While mTOR kinase is negatively  regulated by p53 and AMPK pathway. The UNC-51-like kinase (ULK) acts downstream of the mTOR complex. ULK1 and ULK2 form a large complex, which is also the formation of phagophore, with the mammalian homolog of Vac8, Atg13, Atg11, and the scaffold protein FIP200. Class III PI3K complex, containing Atg13, Atg9, hVps34, and ultraviolet irradiation resistance-associated gene (UVRAG), is required for the induction of autophagy. The Atgs control autophagosome formation through a large complex of Atg12, Atg5 and Atg16L. Atg12 is conjugated to Atg7, Atg10, Atg5, and Atg16L. The LC3 is cleaved at its C-terminus by Atg4 protease to generate the cytosolic LC3-I which is conjugated to phosphatidylethanolamine (PE) also in a ubiquitin-like reaction that requires Atg7 and Atg3. The lipidated form of LC3, known as LC3-II, is attached to the autophagosome membrane. Autophagy and apoptosis are connected both positively and negatively, and extensive crosstalk exists between the two processes. LC3-II interact with Rab which could be the candidate for lysosome biogenesis, and then induced by vesicle-associated membrane protein (VAMP8), synaptosomal-associated protein 29 (SNAP29), and syntaxin-17 (SNX17) to participate in autophagolysosome.

The MAPK signal transduction pathway is one of the most important regulatory mechanisms in eukaryotic cells, and MAPK sub-families JNK participates in multiple stimulation-induced autophagic events, including endoplasmic reticulum stress, caspase (cysteine aspartate-special proteases) inhibition, insulin-like growth factor-1 treatment and exposure to tumor necrosis factor- α (TNF-α). Moreover, JNK has been related to autophagicinduced cell death. The concept of autophagic cell death is redefined as a modality of non-apoptotic or necrotic programmed cell death (PCD) in which autophagy serves as a cell death mechanism. When cells act to down-regulate oncogenic gene expression, oncogenic stress can trigger autophagic cell death as a defense mechanism. Activated JNK induces FoxOs nuclear localization and increases its activity to regulate transcription of other ‘core’ ATG genes.

Function of Cell Autophagy

Autophagy is a fundamental biological process by removing damaged organelles, but disordered autophagy is involved in a variety of diseases including neurodegeneration and microbial infection.

Autophagy is activated in response to adverse environmental conditions such as the deprivation of nutrients, hypoxia, pathogen infection, radiation and oxidative stress as a survival mechanism. This process plays a role in cellular homeostasis, development, and longevity and has many effects on the cellular renovation. It would be reasonable to assume that autophagy can contribute to whole-body rejuvenation. Under many conditions, autophagy is considered as a physiologic cytoprotective or pro-survival mechanism, however, completely uncontrolled or excessive autophagy has been associated with cell death. The characterization of the regulation of autophagy has become relevant because defective autophagy has been linked to aging, neurodegenerative disorders.

Reference:

1. Mizushima, N.; et al. Autophagy: renovation of cells and tissues. Cell. 2011, 147(4): 728-41.

Return to Resources

Inquiry Basket