S-Glutathionylation of estrogen receptor ? affects dendritic cell function.

ABSTRACT: 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 ? (ER?) is linked to myeloproliferation and differentiation, and we observed that its steady-state levels are elevated in Gstp1/p2-/- BMDDCs, indicating a link between GSTP and ER? activities. BMDDCs differentiated by granulocyte-macrophage colony-stimulating factor had elevated ER? levels, which were more pronounced in Gstp1/p2-/- than WT mice. 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?, stimulating ER? S-glutathionylation at cysteines 221, 245, 417, and 447; altering ER?'s binding affinity for estradiol; and reducing overall binding potential (receptor density and affinity) 3-fold. Moreover, in Gstp1/p2-/- BMDDCs, ER? S-glutathionylation was constitutively decreased. Taken together, these findings suggest that GSTP-mediated S-glutathionylation of ER? controls BMDDC differentiation and affects metabolic function in dendritic cells.

SUBMITTER: Zhang J 

PROVIDER: S-EPMC5868252 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature