Copyright ©2010 Baishideng Publishing Group Co.
World J Gastrointest Pharmacol Ther. Oct 6, 2010; 1(5): 94-101
Published online Oct 6, 2010. doi: 10.4292/wjgpt.v1.i5.94
Figure 1
Figure 1 Unfolded protein response. Accumulation of misfolded proteins in the endoplasmic reticulum lumen (e.g. Z α-1 antitrypsin) titrates Bip/Grp78 away from PERK, ATF6 and IRE1. PERK dimerises, becomes phosphorylated and inactivates eIF2α by phosphorylation which blocks translation via eIF2B. ATF4 gene and protein expression is induced leading to ATF4-regulated gene expression, including GADD34 which stimulates protein phosphatase-1 (PP1) and triggers dephosphorylation of eIF2α. Nrf2 is phosphorylated and activated by PERK, translocates to the nucleus and induces antioxidant gene expression. ATF6 is transported to the Golgi and cleaved by the proteases S1P and S2P to generate the active ATF6p50 transcription factor which can activate expression of XBP1 and chaperone genes. IRE1 is phosphorylated, assembles into multimers and via its RNAse activity uses unspliced XBP1 (uXBP1) mRNA as a substrate to generate spliced XBP1 (XBP1s) mRNA which encodes a transcription factor that regulates expression of EDEM1 and chaperones.