Fig. 3.

The UPR can regulate autophagy at different stages in the process, induction, vesicle nucleation, and elongation and maturation. Left hand panel induction of autophagy by the UPR can occur through multiple pathways. Ca²⁺ release from the ER lumen via the inositol 1,4,5-trisphosphate receptor (IP3R) can activate calcium calmodulin kinase II (CaMKII). CaMKII can subsequently phosphorylate and activate AMP kinase (AMPK) which in turn phosphorylates and activates the tuberous sclerosis complex (TSC). TSC inhibits mTORC1 and subsequently relieves mTORC1 inhibition on the ULK1/2 complex. PERK activation results in the non-canonical translation of the transcription factor ATF4. ATF4 can transcriptionally upregulate REDD1 which results in the activation of TSC and subsequent inhibition of mTORC1. ATF4 can also transcriptionally upregulate another transcription factor known as CHOP. CHOP targets expression tribbles-related protein 3 (TRB3). TRB3 can directly inhibit Akt which relieves Akt’s inhibitory effects on TSC, resulting in mTORC1 inhibition and subsequent activation of ULK1/2 complex. CHOP also transcriptionally upregulates ERO1-α. ERO1-α has been shown to stimulate IP3R-mediated Ca²⁺ release from the ER lumen resulting in activation of CaMKII–AMPK–TSC arm leading to mTORC1 inhibition and subsequent activation of ULK1/2 complex. Middle panel the activation of the PI3K complex is an essential step for the induction, nucleation and curvature of the phagophore. Multiple players are involved in the activation of the PI3K complex in response to ER stress. DAPK1 remains in a phosphorylated inactive state under resting conditions. In response to ER stress DAPK1 is dephosphorylated resulting in the activation of its kinase domain. DAPK1 can phosphorylate Beclin’s BH3 domain preventing the inhibitory association of Bcl-2/Bcl-X_L. The PERK–ATF4–CHOP arm can also promote the activation of the PI3K complex. CHOP has been reported to transcriptionally upregulate BH3-only proteins. BH3-only proteins can bind to Bcl-2/Bcl-X_L and displace them from Beclin’s BH3 domain. IRE1-mediated activation of JNK can also result in activation of the PI3K complex. JNK has been shown to phosphorylate Bcl-2/Bcl-X_L and inhibit their association with Beclin1. Right hand panel elongation and maturation of the phagophore requires two important processes to occur, the conversion of LC3I to LC3II and the formation of the ATG12–5–16 complex (see text for details). ATF4 can transcriptionally upregulate LC3 and ATG12, while CHOP can transcriptionally upregulate ATG5. The transcriptional upregulation of these three proteins is essential for the formation of the autophagosome