ATG5-gene

The ATG5 gene (Autophagy related 5 gene) is located on chromosome 6 and encodes the protein of the same name (ATG5 protein). The ATG5 protein is a key protein in the autophagic processing of the cell.

Autophagy is a process by which cells degrade and recycle damaged organelles or misfolded proteins. This "cellular waste" is disposed of when it is completely encased by a double membrane structure produced by the cell, the autophagosome. This autophagosome, along with its contents, fuses with the lysosome in a second step to form the autophagolysosome. In this cell vesicle, the delivered cellular waste is enzymatically degraded. This overall process requires concerted processing of an extensive network of proteins. One of the early steps in autophagosome assembly is the formation of a large multimeric complex called the ATG12-ATG5-ATG16 complex.

During autophagosome assembly, the autophagy protein ATG5is activated by ATG7 and forms a conglomerate with other autophagy proteins, ATG12 and ATG16L1. This complex formation is necessary for the conjugation of LC3-I (microtubule-associated proteins 1A/1B light chain 3B) and PE (phosphatidylethanolamine) to form LC3-II (LC3-phosphatidylethanolamine conjugate). The autophagy protein ATG5 may also act as a pro-apoptotic molecule targeting mitochondria.

At low levels of DNA damage, ATG5 can translocate to the nucleus and interact with survivin. Survivin is a so-called "multitasking protein" that plays a dual role in promoting cell proliferation and further in inhibiting apoptosis. ATG5 is further known to be regulated by various stress-induced transcription factors and protein kinases. Phosphorylation by various kinases is necessary to achieve its active conformation. ATG5 may also be regulated post-translationally by microRNA.

ATG5 comprises three domains: a ubiquitin-like N-terminal domain (UblA), a helix-rich domain (HR) and a ubiquitin-like C-terminal domain (UblB). The three domains are connected by two so-called"linker regions" (L1 and L2).

Apoptosis: In spontaneous apoptosis, ATG5 is N-terminally cleaved by calpain-1 and calpain-2. The cleaved ATG5 translocates from the cytosol to the mitochondria, where it interacts with Bcl-xL, triggering the release of cytochrome C and activating caspases that initiate the apoptotic pathway. This function is independent of its role in autophagy, as it does not require interaction with ATG12.

Cell cycle arrest: In response to DNA damage, ATG5 expression is upregulated, increasing autophagy and preventing caspase activation and apoptosis. ATG5 is also responsible for G2/M arrest and mitotic catastrophe by leading to phosphorylation of key regulators of cell cycle arrest. In addition, ATG5 is able to translocate to the nucleus and interact with survivin to disrupt chromosome segregation by competing antagonistically with the Aurora B ligand.

As a key regulator of autophagy, any suppression of ATG5 protein or loss-of-function mutations in the ATG5 gene negatively affects autophagy. As a result, deficiencies in ATG5 protein and variations in the gene have been associated with various inflammatory and degenerative diseases because aggregates of ubiquitinated targets are not degraded via autophagy.

Polymorphisms within the ATG5 gene have been associated with Behçet's disease, systemic lupus erythematosus (Zhang YM et al. 2015), and lupus nephritis (Zhang YM et al. 2015).

Mutations in the ATG5gene promot1or have been associated with sporadic Parkinson's disease (Chen D et al. (2013) and childhood asthma (Martin LJ et al. 2012).

Downregulation of ATG5 protein and mutations in the ATG5 gene have also been associated with prostate (Li X et al. 2015) gastrointestinal (An CH et al. 2011), as ATG5 plays a role in both cell apoptosis and cell cycle arrest.

In contrast, upregulation of ATG5 has been shown to suppress melanoma tumorigenesis by inducing cell senescence. ATG5 also appears to play a protective role in tuberculosis infection.

1. An CH et al. (2011) Mutational and expressional analyses of ATG5, an autophagy-related gene, in gastrointestinal cancers. Pathology Research and Practice 207: 433-437.
2. Chen D et al (2013). A novel and functional variant within the ATG5 gene promoter in sporadic Parkinson's disease. Neuroscience Letters 538: 49-53.
3. Li X et al (2015). Correlation of autophagy-associated gene Atg5 with tumorigenesis of prostate cancer. National Journal of Andrology 21: 31-34.
4. Martin LJ et al. (2012) Functional variant in the autophagy-related 5 gene promoter [sic] is associated with childhood asthma". PLOS ONE 7: e33454.
5. Maskey D et al. (2013) ATG5 is induced by DNA-damaging agents and promotes mitotic catastrophe independent of autophagy". Nature Communications. 4:2130.
6. Zhang YM et al (2015). Rare Variants of ATG5 Are Likely to Be Associated With Chinese Patients With Systemic Lupus Erythematosus". Medicine 94: e939.
7. Zhang YM et al. (2015) Detecting Genetic Associations between ATG5 and Lupus Nephritis by trans-eQTL. Journal of Immunology Research: 153132.
8. Zheng M et al (2015) "Association of ATG5 Gene Polymorphisms With Behçet's Disease and ATG10 Gene Polymorphisms With VKH Syndrome in a Chinese Han Population". Investigative Ophthalmology & Visual Science. 56 (13): 8280-7. doi:10.1167/iovs.15-18035. PMID 26747760.