Under homeostatic conditions, transmembrane proteins IRE1, ATF6, and PERK reside within the ER membrane, and their lumenal domains bind the protein-folding chaperone BiP. The accumulation of unfolded proteins in the ER triggers alterations of these proteins that result in transcriptional and translational changes in the cell that either deal with the excess unfolded proteins in the ER or promote apoptosis. Upon activation, PERK phosphorylates the translation initiation factor eIF2α, which reduces global translation but promotes translation of the transcription factor ATF4. Activation of IRE1 results in oligomerization, autophosphorylation, and RNA splicing activity. IRE1 specifically splices XBP1 mRNA, which is then relegated and translated. XBP1 then induces transcription of genes involved in the UPR. In response to unfolded proteins, ATF6 is targeted to the Golgi apparatus via vesicular transport. Once in the Golgi, AFT6 is cleaved by S1P and S2P, allowing the cytoplasmic portion of the protein to enter the nucleus and mediate transcription of UPR-associated genes.