pISSN 1976-2283
eISSN 2005-1212

Download original image
Fig. 3. Mammalian unfolded protein response (UPR) pathways. The UPR is triggered by several events, including protein unfolding/misfolding, hypoxia, low adenosine triphosphate levels, ER calcium depletion, and protein/sterol over-expression, causing dissociation of 78 kDa glucose-regulated protein (GRP78) from the three UPR sensors, (A) inositol-requiring enzyme 1α (IRE1α), (B) protein kinase RNA-like endoplasmic reticulum kinase (PERK), and (C) activating transcription factor-6 (ATF6). Activated IRE1α undergoes dimerization and autophosphorylation to generate endogenous RNase activity; in turn, this is responsible for splice truncation of X-box binding protein 1 (XBP1S) mRNA. Additionally, IRE1α may also activate the extrinsic apoptosis pathway, in which tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2)-dependent downstream activation of c-Jun N-terminal kinase (JNK) and caspase-12 takes place. Once activated, PERK undergoes homodimerisation and autophosphorylation to activate eukaryotic translation initiation factor 2 (eIF2α). In turn, this induces ATF4 expression. Separately, dissociation of GRP78, allows ATF6 processing by the Golgi complex, where proteases S1P and S2P cleave an active 50 kDa (p50) ATF6 domain that is free to translocate to the nucleus. Xbp1s, ATF4 and ATF6, as well as other unlisted factors, are responsible for three dominant cell responses to UPR. The folding pathway induces increased expression of molecular chaperones, including GRP78, assisting in compensatory ER protein folding. Alternatively, the cell may respond by increasing ER-associated protein degradation (ERAD) pathway, whereby gene products target and degrade unfolded proteins in the ER. Prolonged UPR results in the activation of the intrinsic apoptosis pathway; this ATF6 and ATF4-dependent process induces C/EBP-homologous protein (CHOP) expression. In turn, CHOP inhibits B-cell lymphoma 2 and induces apoptosis.
Gut Liver 2012;6:149~171 https://doi.org/10.5009/gnl.2012.6.2.149
© Gut and Liver