Significance: Peroxiredoxin 4 (PRDX4) is an endoplasmic reticulum (ER)-resident peroxiredoxin that has the characteristic of coupling hydrogen peroxide (H(2)O(2)) catabolism with oxidative protein folding. This enzymatic arrangement involves the ingenious use of H(2)O(2) as a substrate to streamline protein metabolism.
Recent advances: Mice with compound mutations in Prdx4 and Ero1 have revealed the physiological implication that PRDX4 is a fine-tuned enzymatic mediator of oxidative folding. Remarkably, by simultaneously triggering slow disulfide bond formation and the buildup of H(2)O(2), the lack of PRDX4 and endoplasmic oxidoreductin 1 (ERO1) exposes the thiols of new client proteins to competing H(2)O(2)-mediated oxidation, which leads to an increase in sulfenylated proteins. Such oxygenated thiol derivatives exploit ascorbate as their reductant, thus accelerating its clearance. This relay of events culminates in an altered extracellular matrix (ECM) and a senescent phenotype.
Critical issues and future directions: By combining H(2)O(2) metabolism with oxidative folding, PRDX4 protects nascent proteins from an alternative oxidative fate, and cells from the consequences of having misfolded proteins. This highlights the importance of kinetic-regulated disulfide formation at physiological level, and the presence of an exquisite backup system to protect ER redox homeostasis. By altering ECM architecture, ascorbate depletion in the cells triggers an integrated signaling cascade. This sequence of events is part of a multifaceted response linking the ER and the nucleus, which helps cells to overcome ER redox impairment. Furthermore, the relationship between the protein sulfenylation and ascorbate depletion suggests that it would be interesting to explore the metabolism of ascorbate in pathological conditions accompanied by oxidative stress and a defective ECM.