Fig. 4.

Detailed view of protein secretion pathway. On translocation of the unfolded protein into the ER, multiple chaperones help in folding, glycosylation and formation of disulfide bridges. In the event of an ER overload, accumulation of unfolded proteins leads to ER stress. Three membrane transducers, PERK, Ire1α and ATF6, are bound to GRP78 under normal conditions. ER stress leads to dissociation of GRP78 and subsequent activation of PERK and Ire1α by dimerization and phosphorylation. Activation of ATF6 is by translocation to golgi complex after dissociation from GRP78 where it is cleaved by serine proteases to an active transcription factor ATF6p50. Downstream targets of each of these pathways are shown. AARE amino acid response element; ARE anti-oxidant response element; ERSE endoplasmic reticulum stress element; ATF/CRE activating transcription factor/cAMP responsive element. Abbreviations for the genes are explained in the text