Protein folding in the oxidizing environment of the ER is an energy-requiring process (38, 39). Under non-stressed conditions, newly synthesized proteins exist as unfolded intermediates along the protein-folding pathway. Once ER stress is imposed, such as by depletion of energy, many such folding intermediates become irreversibly trapped in low energy states and accumulate. Unfolded or misfolded proteins in the ER lumen are retrotranslocated through the translocon to the cytoplasm, where they are usually ubiquitinated and degraded by the proteasome (40). This process is called ER-associated degradation (ERAD) and is regulated by the UPR. Proteasomal degradation of ER-associated misfolded proteins is required for protection from UPR activation. Proteasomal inhibition is sufficient to activate the UPR, which can in turn induce transcription of genes encoding several components of ERAD, such as Der1p, Hrd1p/Der3p, Hrd3p, and Ubc7p in yeast (41). The IRE1-XBP1 UPR pathway seems to be critical in regulating ERAD. In mammalian cells, induction of the gene encoding the ER degradation-enhancing a 1,2-mannosidase-like protein, an important ERAD component that is essential for degradation of glycoproteins misfolded in the ER, depends solely on IRE1-XBP1 UPR signaling (42–45). Cells deleted in the IRE1 pathway are defective in ERAD (45).
On the other hand, if the overload of unfolded or misfolded proteins in the ER is not resolved, prolonged activation of the UPR would lead to programmed cell death. Three known proapoptotic pathways emanating from the ER are mediated by IRE1, caspase-12, and PERK/CHOP, respectively, although the mechanisms are unclear (1, 36). Under the ER stress, activated IRE1 can bind c-Jun-N-terminal inhibitory kinase and recruit cytosolic adapter TRAF2, which signals through apoptosis-signaling kinase 1 (ASK1) and the c-Jun N-terminal protein kinase to activate mitochondria/Apaf1-dependent apoptosis (46–48). Caspase-12 is an ER-associated proximal effector of the caspase activation cascade, and cells defective in this enzyme are partially resistant to ER stress-induced apoptosis (49). Under ER stress, activated caspase-12 activates caspase-9, which in turn activates caspase-3, leading to apoptosis (49, 50). CHOP is a b-ZIP transcription factor that induces expression of genes favoring apoptosis in response to ER stress (36). Prolonged UPR activation leads to expression of transcription factor ATF4 through the PERK-eIF2a pathway. ATF4 then induces expression of CHOP, which subsequently activates caspase-3 through unknown intermediates (34, 51).