Nrf2 signaling links ER oxidative protein folding and calcium homeostasis in health and disease.

We report a signaling pathway linking two fundamental functions of the ER, oxidative protein folding, and intracellular calciumregulation. Cells sense ER oxidative protein foldingthrough H2O2, which induces Nrf2 nuclear translocation. Nrf2 regulates the expression of GPx8, an ER glutathione peroxidase that modulates ER calciumlevels. Because ER protein foldingis dependent on calcium, this pathway functions as rheostat of ER calciumlevels. Protein misfolding and calciumdysregulation contribute to the pathophysiology of many diseases, including amyotrophic lateral sclerosis, in which astrocytic calciumdysregulation participates in causing motor neurondeath. In human-derived astrocytesharboring mutant SOD1causative of familial amyotrophic lateral sclerosis, we show that impaired ER redox signaling decreases Nrf2 nuclear translocation, resulting in ER calciumoverload and increased calcium-dependent cell secretion, leading to motor neurondeath. Nrf2 activation in SOD1mutant astrocyteswith dimethyl fumaraterestores calciumhomeostasis and ameliorates motor neurondeath. These results highlight a regulatory mechanism of intracellular calciumhomeostasis by ER redox signaling and suggest that this mechanism could be a therapeutic target in SOD1mutant astrocytes.