-Glutathionylation of estrogen receptor α affects dendritic cell function.

Glutathione -transferase Pi (GSTP) is a thiolase that catalyzes the addition of glutathione (GSH) to receptive cysteines in target proteins, producing an -glutathionylated residue. Accordingly, previous studies have reported that -glutathionylation is constitutively decreased in cells from mice lacking GSTP (/). Here, we found that bone marrow-derived dendritic cells (BMDDCs) from / mice have proliferation rates that are greater than those in their WT counterparts (/). Moreover, / BMDDCs had increased reactive oxygen species (ROS) levels and decreased GSH:glutathione disulfide (GSSG) ratios. Estrogen receptor α (ERα) is linked to myeloproliferation and differentiation, and we observed that its steady-state levels are elevated in / BMDDCs, indicating a link between GSTP and ERα activities. BMDDCs differentiated by granulocyte-macrophage colony-stimulating factor had elevated ERα levels, which were more pronounced in / than WT mice. When stimulated with lipopolysaccharide for maturation, / BMDDCs exhibited augmented endocytosis, maturation rate, cytokine secretion, and T-cell activation; heightened glucose uptake and glycolysis; increased Akt signaling (in the mTOR pathway); and decreased AMPK-mediated phosphorylation of proteins. Of note, GSTP formed a complex with ERα, stimulating ERα -glutathionylation at cysteines 221, 245, 417, and 447; altering ERα's binding affinity for estradiol; and reducing overall binding potential (receptor density and affinity) 3-fold. Moreover, in / BMDDCs, ERα -glutathionylation was constitutively decreased. Taken together, these findings suggest that GSTP-mediated -glutathionylation of ERα controls BMDDC differentiation and affects metabolic function in dendritic cells.