S-Glutathionylation: Indicator of Cell Stress and Regulator of the Unfolded Protein Response

The Unfolded Protein Response (UPR) and pro-apoptotic pathways. The UPR is a complex signaling cascade that can be induced by stress and the accumulation of malfolded proteins in the ER. During homeostasis (upper schematic; blue), protein disulfide isomerase (PDI) promotes the proper folding of immature proteins (yellow strings). The ER-resident protein BiP associates with properly folded proteins and concomitantly inhibits three ER transmembrane proteins, namely, PERK, ATF6, and IRE1. Under conditions of oxidative and nitrosative stress (indicated by ROS/RNS and red background in lower ER schematic), PDI is modified (see text for discussion) and rendered inactive, and unfolded proteins (yellow strings) accumulate in the ER. BiP dissociates from improperly folded proteins and concomitantly surrenders negative regulatory interactions with PERK, ATF6, and IRE1. PERK thereby phosphorylates and inactivates (blunt arrow) eukaryotic translation initiation factor eIF2α, the phosphorylation of which is also associated with transcriptional activation of genes involved in the UPR. This transcriptional activation, which is also promoted by the activation of ATF6 and IRE1, can drive pro-apoptotic signaling, particularly through activation of CHOP (see text for details). IRE1 can also interact with TRAF2, which can function pro-apoptotically through association with ASK1 and JNK (see text; also see Figure 2). A third route to apoptosis is offered by caspase activity; intriguingly, regulation of caspase activity (particularly that of CASP3) may also be a function of GST.