Atg family proteins

Phosphatidylinositol 3-kinase (PI3K) phosphorylates the phosphatidylinositol (PI) in the membrane lipid to create phosphatidylinositol 3-phosphate (PI3P). Class III PI3K activity, called Vps34, is necessary for the progress of autophagy.
Vps34 forms a complex with Vps15 (protein kinase), Vps30/Atg6 (Beclin-1 in mammals), and Atg14. If even one of these subunits is rendered defective, autophagy will not be induced. As well, because lipid kinase activity in Vps34 is necessary for autophagy to take place, it is thought that the PI3P produced thereby plays some role in autophagy. Beclin 1/hVps34/p150/Rubicon/UVRAG complex involves in autophagosome maturation. On the other hand, Beclin 1 has been reported to be defective in various forms of cancer (breast, ovarian, prostate), and it is known that cancer is frequent in Beclin 1 hetero-defective mice. As well, DNA defects related to cancer have been found in the Beclin 1 binding protein UVRAG.

It has not yet known where the initiation of autophagy takes place. In the yeast, however, autophagosome formation is suggested to start at the pre-autophagosomal structure (PAS). Atg9 is thought to be involved in the early phase of PAS formation, since many Atg proteins are not localized in the PAS in the budding yeast lacking ATG9.

Atg2-Atg18 complex binds to Atg9 on the surface of the PAS and Atg18 is known to interact with PI3P. But, the function of Atg2-Atg18 complex is still not known. In the yeast with mutated ATG18 and ATG2, Atg9 is highly accumulated at the PAS. Meanwhile, Atg9 is not localized at the surface of autophagosome. These findings suggest there must be mechanisms for Atg9 to detach from the PAS surface. Atg2-Atg18 complex may be involved in this process.

As we have seen so far, it is now understood that the seventeen varieties of Atg proteins necessary for the formation of an autophagosome act as at least five functional aggregates. There are many issues yet to be understood regarding the role of each complex and the interactions among complexes, but in recent years more and more factors related to autophagy, beginning with Atg conjugated proteins, continue to be identified.

UVRAG, related to UV resistivity, is receiving renewed attention as a Beclin 1 conjugated protein, and it is now clear that it is involved in the formation of the autophagosome through the activation of PI3K. p62/a170/SQSTM1 (p62), which interacts with Atg8 (LC3), is a scaffolding protein for signal transmission through ERK or PKC; because it has a ubiquitin binding domain at its C-terminal, it suggests crosstalk between ubiquitin proteasome degradation through p62 and autophagy. As well, regarding pathogen elimination through autophagy, it is known that LRGM/LRG-47, a variety of GTP conjugated protein with the toll-like receptor and IFN-γ inductor important for pathogen recognition, is used in innate immunity.

In this way, spurred by research into autophagy, new and diverse interactions among biological phenomena have become visible.

In the future, expectations will rest on approaches using Atg-factor defective yeast strains and Tg/KO mice, as well as development of factor monitoring tools such as antibodies to Atg proteins and conjugate factors, and fluorescent protein fusion proteins.

Autophagy was first discovered in yeast as a form of cellular self-digestion for the purpose of providing nutrients to the cell in order to survive starvation. Research in autophagy has been expanding from its initial discovery in yeast, as a form of cellular self digestion, to having implications in major drug discovery pipelines. Recent researches and advances have shown an association of mammalian autophagy with diseases such as neurodegenerative disease, infection disease, cardiac disease as well as cancers.