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. 2012 Oct;4(10):a008839. doi: 10.1101/cshperspect.a008839

Figure 2.

Figure 2.

Schematic for the three major subtypes of autophagy—macroautophagy, chaperone-mediated autophagy, and microautophagy. The mammalian target of rapamycin (mTOR) kinase, the principal regulator of macroautophagy, is activated by inhibiting the tuberous sclerosis complex (TSC1) and TSC2, thereby increasing the function of the GTP-binding protein Rheb (A). Insulin or growth factors suppress autophagy by activating the class I phosphatidylinositol 3 kinase (PI3K)–Akt/protein kinase B (PKB) pathway. Abundant intracellular stores of amino acids and ATP suppress autophagy by inhibiting AMP-activated protein kinase (AMPK), an activator of the TSC complex. Macroautophagy is orchestrated by complexes composed of autophagy gene (Atg)-related proteins, which coordinate specific steps in autophagy induction and sequestration as described in the text. The process is initiated when an “isolation” membrane is created from a preautophagosomal structure (PAS) under the direction of the class III PI3K complex and Atg proteins, including Beclin 1 (Atg6) (B). Two ubiquitin-like protein conjugation pathways (C) direct the expansion of the isolation membrane as it sequesters a region of cytoplasm and organelles into a double-membrane-limited autophagosome (AP). Microtubule-associated protein light chain 3-II (LC3-II), formed by phosphoethanolamine conjugation of LC3-I, translocates to the autophagosome membrane (C). Digestion of the sequestered cytoplasmic cargo is initiated when a lysosome (Ly) fuses with the outer membrane of the autophagosome to form an autophagolysosome (APL) and lysosomal hydrolases are introduced. The completion of substrate digestion within autolysosomes (AL) ultimately results in lysosome retrieval. In chaperone-mediated autophagy, cytosolic proteins containing a KFERQ motif are selectively chaperoned (Chap) and delivered to the lysosomal lumen for degradation through the binding to LAMP2 located on the lysosomal membrane. In microautophagy, small quantities of proteins or organelles directly enter lysosomes by invagination of the lysosomal or endosomal membrane.