RT Journal Article
SR Electronic
T1 Nrf2 signaling links ER oxidative protein folding and calcium homeostasis in health and disease
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900563
DO 10.26508/lsa.201900563
VO 2
IS 5
A1 Veronica Granatiero
A1 Csaba Konrad
A1 Kirsten Bredvik
A1 Giovanni Manfredi
A1 Hibiki Kawamata
YR 2019
UL https://www.life-science-alliance.org/content/2/5/e201900563.abstract
AB We report a signaling pathway linking two fundamental functions of the ER, oxidative protein folding, and intracellular calcium regulation. Cells sense ER oxidative protein folding through H2O2, which induces Nrf2 nuclear translocation. Nrf2 regulates the expression of GPx8, an ER glutathione peroxidase that modulates ER calcium levels. Because ER protein folding is dependent on calcium, this pathway functions as rheostat of ER calcium levels. Protein misfolding and calcium dysregulation contribute to the pathophysiology of many diseases, including amyotrophic lateral sclerosis, in which astrocytic calcium dysregulation participates in causing motor neuron death. In human-derived astrocytes harboring mutant SOD1 causative of familial amyotrophic lateral sclerosis, we show that impaired ER redox signaling decreases Nrf2 nuclear translocation, resulting in ER calcium overload and increased calcium-dependent cell secretion, leading to motor neuron death. Nrf2 activation in SOD1 mutant astrocytes with dimethyl fumarate restores calcium homeostasis and ameliorates motor neuron death. These results highlight a regulatory mechanism of intracellular calcium homeostasis by ER redox signaling and suggest that this mechanism could be a therapeutic target in SOD1 mutant astrocytes.