The UPR involves three main signaling pathways, each regulated by a distinct sensor protein in the ER membrane:
PERK (Protein kinase RNA-like endoplasmic reticulum kinase): PERK activation leads to phosphorylation of eIF2α, which reduces global protein synthesis, thus decreasing the load of new proteins entering the ER. IRE1 (Inositol-requiring enzyme 1): IRE1 splices XBP1 mRNA, producing a transcription factor that upregulates genes involved in protein folding, secretion, and ER-associated degradation (ERAD). ATF6 (Activating transcription factor 6): Upon activation, ATF6 translocates to the Golgi, where it is cleaved to release a cytoplasmic fragment that acts as a transcription factor to increase the expression of UPR target genes.
