| First Author | Zhang J | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 12 | Pages | 4366-4380 |
| PubMed ID | 29374060 | Mgi Jnum | J:262854 |
| Mgi Id | MGI:6157196 | Doi | 10.1074/jbc.M117.814327 |
| Citation | Zhang J, et al. (2018) S-Glutathionylation of estrogen receptor alpha affects dendritic cell function. J Biol Chem 293(12):4366-4380 |
| abstractText | 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 (ERalpha) 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 ERalpha activities. BMDDCs differentiated by granulocyte-macrophage colony-stimulating factor had elevated ERalpha 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 ERalpha, stimulating ERalpha S-glutathionylation at cysteines 221, 245, 417, and 447; altering ERalpha's binding affinity for estradiol; and reducing overall binding potential (receptor density and affinity) 3-fold. Moreover, in Gstp1/p2(-/-) BMDDCs, ERalpha S-glutathionylation was constitutively decreased. Taken together, these findings suggest that GSTP-mediated S-glutathionylation of ERalpha controls BMDDC differentiation and affects metabolic function in dendritic cells. |
