Review Article

The Impact of Autophagy on Cell Death Modalities

Figure 2

Autophagy is negatively regulated by the phosphatidylinositol 3-kinase (PI3 K)/Akt signaling pathway, which activates mammalian target of rapamycin (mTOR) in response to growth factors and also phosphorylates Beclin 1. The adenosine 5′-monophosphate-activated protein kinase (AMPK) negatively regulates mTOR thereby acting as a positive regulator of autophagy in response to AMP levels. mTOR resides in the mTOR signaling complex (mTORC1), which regulates the mammalian uncoordinated-51-like protein kinase (ULK1) complex, consisting of ULK1, ATG13, ATG101, and RB1CC1. Autophagy is also regulated by the Beclin 1 complex, consisting of Beclin 1, class III phosphatidylinositol-3-kinase (VPS34 or PI3KC3) and ATG14L or UVRAG. Stimulation of the Beclin 1 complex generates phosphatidylinositol-3-phosphate (PI3P), which triggers autophagosomal nucleation. Autophagosome membrane elongation is regulated by ubiquitin-like conjugation systems. ATG12 is conjugated to ATG5 by ATG7 and ATG10 enzymes, which results in the formation of the ATG5-ATG12-ATG16L1 complex. The Atg8 conjugation system involves microtubule-associated protein-1 light chain 3 (LC3, ATG8). LC3 and other Atg8 homologues are modified with the cellular lipid phosphatidylethanolamine. Pro-LC3 is cleaved by ATG4B to generate the LC3-I form. ATG4D may similarly process other Atg8 homologs. Lipid conjugation of LC3-I occurs from the action of ATG7 and ATG3 activities. The conversion of LC3-I (free form) to LC3-II (lipid-conjugated form) is a major step in autophagosome formation. Antiapoptotic Bcl-2 family proteins can interact with the autophagy machinery at the site of Beclin1, resulting in inhibition of autophagy. The tumor suppressor protein p53 and activated caspases potentially interact with the autophagy machinery at the indicated sites. Caspase processing can result in activation of autophagy (e.g., Atg4D) or inhibition of autophagy (e.g., Beclin 1, Atg3). Additionally, Atg12 and a cleavage product of Atg5 can act as proapoptotic mediators by antagonizing antiapoptotic Bcl-2 family proteins.
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