S-Glutathionylation of estrogen receptor α affects dendritic cell function

Glutathione S-transferase Pi (GSTP) is a thiolase that catalyzes the addition of glutathione (GSH) to receptive cysteines in target proteins, producing an S-glutathionylated residue. Accordingly, previous studies have reported that S-glutathionylation is constitutively decreased in cells from mice lacking GSTP (Gstp1/p2(-/-)). Here, we found that bone marrow-derived dendritic cells (BMDDCs) from Gstp1/p2(-/-) mice have proliferation rates that are greater than those in their WT counterparts (Gstp1/p2(-/-)). Moreover, Gstp1/p2(-/-) BMDDCs had increased reactive oxygen species (ROS) levels and decreased GSH:glutathione disulfide (GSSG) ratios. Estrogen receptor alpha (ER alpha) is linked to myeloproliferation and differentiation, and we observed that its steady-state levels are elevated in Gstp1/p2(-/-) BMDDCs, indicating a link betweenGSTPand ER alpha activities. BMDDCs differentiated by granulocyte-macrophage colony-stimulating factor had elevated ER alpha levels, which were more pronounced in Gstp1/p2(-/-) thanWTmice. When stimulated with lipopolysaccharide for maturation, Gstp1/p2(-/-) 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 ER alpha, stimulating ER alpha S-glutathionylation at cysteines 221, 245, 417, and 447; altering ER alpha's binding affinity for estradiol; and reducing overall binding potential (receptor density and affinity) 3-fold. Moreover, in Gstp1/p2(-/-) BMDDCs, ER alpha S-glutathionylation was constitutively decreased. Taken together, these findings suggest that GSTP-mediated S-glutathionylation of ER alpha controls BMDDC differentiation and affects metabolic function in dendritic cells.