S-Glutathionylation of estrogen receptor α affects dendritic cell function

J Biol Chem. 2018 Mar 23;293(12):4366-4380. doi: 10.1074/jbc.M117.814327. Epub 2018 Jan 26.

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 α (ERα) 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 ERα activities. BMDDCs differentiated by granulocyte-macrophage colony-stimulating factor had elevated ERα 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 ERα, stimulating ERα S-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 Gstp1/p2-/- BMDDCs, ERα S-glutathionylation was constitutively decreased. Taken together, these findings suggest that GSTP-mediated S-glutathionylation of ERα controls BMDDC differentiation and affects metabolic function in dendritic cells.

Keywords: S-glutathionylation; dendritic cell; energy metabolism; estrogen; estrogen receptor; glutathione; glutathione S-transferase; myeloproliferation; redox signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Dendritic Cells / cytology
  • Dendritic Cells / physiology*
  • Estrogen Receptor alpha / metabolism*
  • Glutathione / metabolism*
  • Glutathione S-Transferase pi / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oxidative Stress
  • Protein Processing, Post-Translational*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction

Substances

  • Estrogen Receptor alpha
  • Gstp2 protein, mouse
  • Reactive Oxygen Species
  • Glutathione S-Transferase pi
  • Gstp1 protein, mouse
  • Glutathione