FIGURE 2.

Autophagy induction and possible mechanisms of action of chemical modulators

Autophagosome formation can be initiated via mTOR inhibition or AMPK activation that results in the activation of the ULK complex (ULK1-ATG13-FIP200). mTOR can be inhibited by specific inhibitors including rapamycin, Torin1, and PP242, which therefore induce autophagy. There are some autophagy-inducing agents such as Trehalose and lithium that act through a mTOR-independent pathway that has not been elucidated. After the ULK complex is activated, it targets a class III PI3K complex, consisting of beclin 1, VPS15, VPS34, and ATG14 to promote the local production of PI3P that is specific to autophagosomes. Class III PI3K activity can be inhibited by 3-methyladenine (3-MA), inhibiting autophagy. For autophagosome elongation and formation, the ATG12-ATG5-ATG16 localizes to the outer membrane, where it facilitates the lipidation of LC3 with phosphatidylethanolamine (PE). By cleavage of pro-LC3 by ATG4, LC3-I is formed. Then, LC3-I is processed by ATG7 and ATG3 to be conjugated to PE and form LC3-II. Lanthionine ketimine (LK) compounds induce conversion from LC3-I to LC3-II through a mechanism that is not completely known.