![]() ![]() Additional interactions are proposed between PDI family members, represented here by ERp57 (PDIA3) and ERp72 (PDIA4). The ox1 form predominates under normal ER lumenal conditions, whereas the ox2 form is generated with the ER lumen becomes hyperoxidizing. ERO1 also undergoes redox-mediated regulation by existing in two oxidized states, indicated here as ERO1 ox1 and ERO1 ox2, wherein the ox1 state has oxidized catalytic cysteines and reduced regulatory cysteines, and is therefore active, versus ox2, which has oxidized regulatory cysteines and is therefore inactive. Both PRDX4 and GPx7/8 likely use H 2O 2 generated by ERO1 or NADPH oxidase 4 (NOX4) to reoxidize PDI. PDIs are maintained in an oxidized state by electron transfer to 1) ERO1, generating H 2O 2 in the process 2) PRDX4, which neutralizes H 2O 2 and 3) GPx7/8, which also neutralizes H 2O 2. The main ER resident proteins controlling oxidative folding are the PDI family members. The extent to which GSSG influences protein folding remains less understood. It is characterized by a high preponderance of GSSG, which is generated by ER-localized GPx7/8 as a method of neutralizing H 2O 2. The ER lumen must be sufficiently oxidizing to maintain protein folding. Mechanisms maintaining the oxidative capacity of the ER lumen. In this review, we discuss oxidative protein folding in the ER, NADPH generation by the major pathways that mediate it, and ER-localized systems that can link the two processes to connect ER function to metabolic activity.Įndoplasmic recticulum glutathione metabolism nicotinamide adenine dinucleotide phosphate redox. For this reason, NADPH might serve as a mediator linking metabolic activity to ER homeostasis and stress, and represent a novel form of mitochondria-to-ER communication. A key molecule central to both processes is NADPH, which is produced by reduction of NADP+ during nutrient catabolism and which in turn drives the reduction of components such as glutathione and thioredoxin that influence the redox potential in the ER lumen. These parallel needs for protein oxidation in the ER and nutrient oxidation in the cytosol and mitochondria raise the possibility that the two processes compete for electron acceptors, even though they occur in separate cellular compartments. Simultaneously, nutrients are oxidized in the cytosol and mitochondria to power ATP generation, reductive biosynthesis, and defense against reactive oxygen species. Both protein oxidation itself and other essential ER processes, such as the degradation of misfolded proteins and the sequestration of cellular calcium, are tuned to the ER redox state. The endoplasmic reticulum (ER) lumen is highly oxidizing compared to other subcellular compartments, and maintaining the appropriate levels of oxidizing and reducing equivalents is essential to ER function. ![]()
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