The endoplasmic reticulum (ER) is the site of synthesis and folding of membrane and secretory proteins. Stringent quality control ensures that only correctly folded proteins exit the ER, while unfolded or misfolded proteins are retained and degraded. A number of biochemical and physiological stimuli can lead to the accumulation of aberrantly folded proteins in the ER. To cope with the stress of accumulated misfolded proteins, the ER has evolved highly intricate and specific pathways involving the cytosol and nucleus, known as the unfolded protein response (UPR).
At the center of the UPR are three transmembrane ER stress sensors-inositol-requiring 1 (IRE1), PKR-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). In unstressed cells the lumenal domains of the stress sensors form a stable complex with the ER chaperone-immunoglobulin binding protein (BiP). Perturbation of protein folding promotes reversible dissociation of BiP from the stress sensors, which then participate in the UPR pathway. PERK, an ER-transmembrane kinase phosphorylates the subunit of eukaryotic translation initiation factor 2 (eIF2) resulting in translational repression. This likely alleviates the stress in the ER by reducing the flux of newly synthesized proteins. The selective translation of transfactor activating transcription factor 4 (ATF4) results in the transcription of other UPR genes. The endonuclease function of IRE1 is activated after its dissociation from BiP. IRE1 then mediates the cleavage step in the nonconventional splicing of X-box binding protein 1 (XBP1) mRNA to produce XBP1 protein that is a potent transcription factor. The processing of XBP1 mRNA is an obligate step in the UPR pathway. The sensor ATF6 is a membrane bound transcription factor that undergoes cleavage and then activates genes to ameliorate ER stress.
Activation of caspase-12 is specifically induced by insult to the ER. In ER stress, a specific cascade involving caspase-12, -9, and -3 is activated, culminating in apoptosis of the cell in a cytochrome c-independent manner.
The ER stress pathway highlights the key molecular events involved in the unfolded protein response.