Figure 2.

Possible autophagy signaling pathway after ischemic stroke and possible autophagy-regulating mechanism of circRNAs. Intracellular Ca²⁺ is increased during IS. Increased Ca²⁺ triggers ER stress and activates CaMKK, which in turn phosphorylates and activates AMPK. AMPK mediates the initiation of autophagy through the inhibition of mTORC1. Growth factors can activate PI3K. Then PI3K activates Akt through phosphorylation, and subsequently, the activated Akt directly phosphorylates and thereby inhibits TSC1/2. The Akt-dependent phosphorylation results in the dissociation of TSC1/2 from the lysosome, where Rheb is localized, promoting Rheb activation. Since GTP-bound Rheb is a potent mTORC1 activator, inhibition of TSC1/2 by AKT-dependent phosphorylation results in mTORC1 activation. Autophagy is inhibited by activated mTORC1. However, under conditions of growth factors or amino acid insufficiency during IS, mTORC1 activity is reduced and induces autophagy. Hypoxia caused by IS activates HIF-1α and induces autophagy through BNIP3 and p53. During IS, an increased AMP/ATP ratio activates LKB1 kinase, which in turn phosphorylates and activates AMPK. AMPK mediates the induction of autophagy through the inhibition of mTORC1. Activation of the p38 MAPK signaling pathway in IS phosphorylates GSK3β, which can subsequently activate ENDOG and TSC1/2. Activated TSC1/2 promotes the initiation of autophagy by inhibiting mTORC1. JNK activation modulates autophagy by promoting Bcl-2/Bcl-xL phosphorylation and upregulating DRAM. Beclin-1 interacts with Bcl2 through its unique BH3 pattern to form the Bcl2-Beclin-1 complex via promoting Beclin-vps34-p50 complex dissociation to inhibit autophagy. DRAM can promote autophagy by stimulating autophagosome-lysosome fusion. Overexpression of circSHOC2 inhibits the initiation of autophagy. Overexpression of circ-FoxO3 can promote the initiation of autophagy through inhibition of mTORC1. Overexpression of circ_016719 promotes nucleation of autophagy.