Fig. 1Steps of autophagy induction and autophagosome formation. Mammalian target of rapamycin complex 1 (mTORC1) inhibition by nutrient deprivation or rapamycin treatment induces the dephosphorylation of UNC51-like kinase 1 (ULK1), which phosphorylates autophagy-related gene 13 (Atg13) and FIP200. When autophagy is activated, Beclin 1 is liberated from Bcl-2 and induces autophagosome formation with Vps34, Vps15, and Atg14L or autophagosome maturation with Vps34, Vps15, and ultraviolet radiation resistance-associated gene (UVRAG). Phosphatidylinositol-3-phosphate (PI3P) produced by Vps34 is important in the recruitment of Atg proteins to initiate autophagosome formation. The Atg system is similar to the ubiquitination system. Atg12 and light chain 3 (LC3) are ubiquitin-like proteins. Atg7 is similar to E1. Atg10 and Atg 3 are E2-like enzymes. The Atg12-Atg5-Atg16L1 complex behaves like E3 ligase. LC3-II, formed by LC3 conjugation to its lipid target (phosphatidylethanolamine, PE), is a receptor for p62 which binds to ubiquitinated proteins for proteolytic degradation.
Fig. 2Expression of unfolded protein response (UPR)-related genes in autophagy-deficient islets. Pancreatic islets were isolated from Atg7Δβ-cell and Atg7F/F mice. (A) Real-time reverse transcription polymerase chain reaction was performed using primer sets specific for diverse genes of UPR. (B) Susceptibility of autophagy-deficient islet cells to endoplasmic reticulum (ER) stressors. Primary pancreatic islets were treated with thapsigargin (Tg; left) or palmitic acid (PA; right), and cell death was determined by measuring released oligonucleosomes in the culture supernatant. Autophagy-deficient β-cells were more susceptible to ER stress-induced cell death, probably due to insufficient UPR gene expression. Atg, autophagy-related gene. aP<0.05; bP<0.01; cP<0.001. Adapted from Quan W, et al. Diabetologia 2012;55:392-403, with permission from Springer Science+Business Media [15].
Fig. 3Blood glucose level and β-cells of Atg7Δβ-cell-ob/ob mice. (A, B) Apoptotic β-cell number (A) and β-cell mass (B) are shown. (C) Fasting blood glucose levels were determined in Atg7F/F-ob/w (n=7), Atg7Δβ-cell-ob/w (n=6), Atg7F/F-ob/ob (n=5), and Atg7Δβ-cell-ob/ob mice (n=4). (D) Intraperitoneal glucose tolerance test was performed, and the results from Atg7Δβ-cell-ob/ob mice were compared with those of other types of mice (n=4, each group). Atg, autophagy-related gene. aP<0.05; bP<0.01; cP<0.001. Adapted from Quan W, et al. Diabetologia 2012;55:392-403, with permission from Springer Science+Business Media [15].