Figure 1.

Signaling and gene regulation of the canonical cell autonomous unfolded protein response (UPR). The accumulation of unfolded proteins in the endoplasmic reticulum (ER) induces the three signaling cascades initiated by the transmembrane proteins: IRE1, ATF6 and PERK. This results in the inhibition of protein translation through PERK and the production of active transcription factors: XBP1s, ATF6 and ATF4 via IRE1, ATF6 and PERK, respectively. Upon translocation to the nucleus, XBP1s and ATF6 bind in different compositions to specific promoter sequences, including ERSE, ERSE-II and UPRE, and initiate transcription of multiple UPR genes, including ER chaperones and ERAD genes. Nuclear ATF4 binds the CARE promoter motif and induces CHOP transcription, which in turn increases GADD34 levels, thereby providing negative feedback in the PERK pathway. For details see main text.