FIGURE 1.

Overview of autophagy and its regulation. Nutrient sensing in autophagy induction is multifaceted. Activation of the ULK serine threonine kinase complex induces autophagy by promoting release of BECN1 from BCL2 inhibitory heterotetramers, and promoting the association of BECN1 with ATG14, VSP15, and VSP34 in Class III PI3K complex I. This complex is responsible for initiating isolation membrane formation. AMPK activation in response to cellular energy status activates ULK complex by phosphorylation of ULK1 and ATG13. Activation of autophagy is antagonized by mTOR inhibition of AMPK, ULK complex, and Class III PI3K complex I and II. mTOR activity is maintained by intracellular leucine, arginine, and methionine levels. Leucine and arginine inhibit SESTRIN and CASTOR, respectively, to promote GATOR2 inhibition of GATOR1, a key negative regulator of mTOR activity. Methionine, through production of SAM inhibits SAMTOR to suppress GATOR1 activity. Activation of growth factor signaling via hormones upstream of mTOR (e.g., leptin, insulin, and IGF1) further suppresses autophagy. GHRL signaling in contrast can activate AMPK to promote autophagy. Maintenance of protein acetylation by acetyltransferases is enabled by ready supply of acetyl-coA and suppresses the activity of ATG5-ATG12 complex further limiting autophagy induction. Activation of sirtuins by elevation of NAD⁺ levels promotes autophagy by reducing such inhibitory acetylation and enabling ATG5-ATG12 complex to lipidate LC3.