Fig. 2.

Molecular regulation of autophagy. Autophagy responds to negative regulation by growth factor stimuli that regulate the Class I phosphatidylinositol-3-kinase (PI3K/AKT) pathway, which upregulates the mTOR pathway. mTOR resides in a macromolecular complex (mTORC1): this multi-protein complex is activated by nutrient associated signals including amino acids and growth factors, and negatively regulates autophagy by interacting with the ULK1 complex. Autophagy also responds to regulation by depletion of cellular energy charge through the increased activity of the 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK). In response to elevated AMP levels, AMPK inactivates mTORC1 and activates ULK1, which can activate Beclin1 and promote the trafficking of mATG9. The initiation of autophagosome formation is also regulated by the autophagy protein Beclin 1 (Atg6). Beclin 1 associates with a macromolecular complex that includes hVps34, a class III phosphatidylinositol-3 kinase (PI3KC3), p150, and ATG14L. The Beclin1 complex produces PI3P which recruits assessory factors in autophagosome formation, including WIPI2. Autophagosome elongation requires two ubiquitin-like conjugation systems, the ATG5-12 conjugation system, and the ATG8 (LC3) conjugation system. Autophagy protein LC3-II remains associated with the maturing autophagosome.