Fig. 2: Mild ER stress and adaptive UPR signaling.

Mild ER stress triggers adaptive UPR signaling composed of three main branches; PERK, IRE1, and ATF6. As shown in the figure, the PERK–eIF2α axis promotes selective translation of some genes such as ATG12, which along with ATG16 and ATG5 induces lipidation and activation of ATG8, resulting in autophagy of the ER (ER-phagy). PERK-mediated phosphorylation of eIF2α also suppresses the translation to reduce protein overload in the ER. Likewise, the PERK–PI3K–AKT1 axis blocks apoptosis, and the PERK–RAF1–RRAS–MAP kinases cascade activates two cardinal transcription factors, ATF4 and NFE2L2, which transactivate genes encoding proteins involved in autophagy. mTOR complex 1 (mTORC1) is a negative regulator of autophagy via suppression of the ULK1 signaling complex to beclin1(BECN1). Inhibition of mTORC1 by DDIT4 can in turn activate autophagy. NFE2L2-induced genes encode components of autophagy machinery further fueling autophagy. NFE2L2 also upregulates antioxidant genes including CYP2D6 and CALCOCO2. Among ATF4-upregulated genes are those encoding ER chaperones such as HSPA5 and other enzymes to facilitate protein folding in the ER. Activation of the IRE1 branch during the UPR leads to the activation of some key transcription factors (see figure). Thus IRE–TRAF2 axis can activate i MAPK8 and JUN, which relocate to the nucleus and upregulate ATGs and BECN1 genes. IRE1-mediated activation of the AMPK also boosts autophagy and blocks apoptosis. Most importantly, IRE1 via its inherent RNAse activity produces mRNA encoding the transcription factor XBP1s, which in the nucleus upregulates autophagy-associated genes and proteins involved in the ERAD. During the UPR, ATF6 is processed in the Golgi to produce the active transcription factor which in turn can also upregulate genes encoding chaperones and ERAD proteins as well as DAPK1 and DDIT3 genes, with a role in autophagy. Overall, the adaptive UPR suppresses ER stress via induction of corrective autophagy, inhibition of apoptosis, and activation of the ERAD. There is also an upregulation of ER chaperones, inhibition of additional protein translation, and an enhancement of ER capacity all serving to boost the correct folding of proteins.