Selenoprotein N (SEPN1) is a broadly expressed resident protein of the endoplasmic reticulum (ER) whose loss-of-function inexplicably leads to human muscle disease. We found that SEPN1 levels parallel those of endoplamic reticulum oxidoreductin 1 (ERO1), an ER protein thiol oxidase, and that SEPN1's redox activity defends the ER from ERO1-generated peroxides. Moreover, we have defined the redox-regulated interactome of SEPN1 and identified the ER calcium import SERCA2 pump as a redox-partner of SEPN1. SEPN1 enhances SERCA2 activity by reducing luminal cysteines that are hyperoxidized by ERO1-generated peroxides. Cells lacking SEPN1 are hypersensitive to ERO1 overexpression and conspicuously defective in ER calcium re-uptake. After being muscle-transduced with an adeno-associated virus driving ERO1α, SEPN1 knockout mice unmasks a myopathy that resembles the dense core disease due to human mutations in SEPN1, whereas the combined attenuation of ERO1α and SEPN1 enhances cell fitness. These observations reveal the involvement of SEPN1 in ER redox and calcium homeostasis and that an ERO1 inhibitor, restoring redox-dependent calcium homeostasis, may ameliorate the myopathy of SEPN1 deficiency.

Angiogenesis is the process of blood vessel growth. The angiogenic switch consists of new blood vessel formation that, in carcinogenesis, can lead to the transition from a harmless cluster of dormant cells to a large tumorigenic mass with metastatic potential. Hypoxia, that is, the scarcity of oxygen, is a hallmark of solid tumors to which they adapt by activating hypoxia‐inducible factor‐1 (HIF‐1), a transcription factor triggering de novo angiogenesis. HIF‐1 and the angiogenic molecules that are expressed upon its activation are modulated by redox status. Modulations of the redox environment can influence the angiogenesis signaling at different levels, thereby impinging on the angiogenic switch. This review provides a molecular overview of the redox‐sensitive steps in angiogenic signaling, the main molecular players involved, and their crosstalk with the unfolded protein response. New classes of inhibitors of these modulators which might act as antiangiogenic drugs in cancer are also discussed.

Significance: Selenoprotein N (SEPN1) is a type II transmembrane protein of the endoplasmic reticulum (ER) that senses luminal calcium through an EF-hand domain. On calcium depletion, a SEPN1 oligomer, prevalent under basal calcium concentrations, dissociates to generate a monomeric polypeptide that has enhanced redox trapping potential for its target the calcium pump, SERCA2, as well as for many additional interactors, indicating enhanced reductase activity. Our studies not only support that SEPN1 is one of the long-sought reductases of the ER, but also identify a feedback mechanism through which SEPN1 senses the luminal calcium level to modulate downstream signal transduction. Our results suggest that SEPN1 regulates the SERCA-mediated replenishment of ER calcium stores, a crucial mechanism for excitation-contraction coupling in skeletal muscle.

Significance: Peroxiredoxin 4 (PRDX4) is an endoplasmic reticulum (ER)-resident peroxiredoxin that has the characteristic of coupling hydrogen peroxide (H₂O₂) catabolism with oxidative protein folding. This enzymatic arrangement involves the ingenious use of H₂O₂ 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 H₂O₂, the lack of PRDX4 and endoplasmic oxidoreductin 1 (ERO1) exposes the thiols of new client proteins to competing H₂O₂-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 H₂O₂ 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. Antioxid. Redox Signal. 18, 1666–1674.