Modulation of Apoptosis Pathways by Oxidative Stress and Autophagy in β Cells

Figure 7

Interactions of signaling by ER stress, oxidative stress, and cytokines with the pathways of autophagy: Induction of autophagy requires the assembly of Beclin-1 with class III PI 3 kinase (Vps34) and UVRAG. Rapamycin is an activator of autophagy as it is negatively regulated by class I PI 3 kinase through mammalin target of rapamycin (mTOR). The elongation step involves two ubiquitin-like conjugation system. ATG12 is activated by E1-like ATG7, transferred to E2-like ATG10 and conjugated to ATG5. Similarly, LC3-I is activated by E1-like ATG7, transferred to E2-like ATG3, and conjugated to phosphatidylethanolamine (PE). Inhibitors of autophagy include 3 methyl adenine which inhibits class III PI 3-K and bafilomycin A1 which inhibits the formation of autophagolysosome. Interaction of Bcl-2 with Beclin-1 keeps the autophagic pathway under control. CREB induces the expression of Bcl-2 which is downregulated by ER stress, oxidative stress and cytokines through JNK.