Palmitoylation Regulates 17β-Estradiol-Induced Estrogen Receptor-α Degradation and Transcriptional Activity

The estrogen receptor-alpha (ER alpha) is a transcription factor that regulates gene expression through the binding to its cognate hormone 17 beta-estradiol (E2). ER alpha transcriptional activity is regulated by E2-evoked 26S proteasome-mediated ER alpha degradation and ER alpha serine (S) residue 118 phosphorylation. Furthermore, ER alpha mediates fast cell responses to E2 through the activation of signaling cascades such as the MAPK/ERK and phosphoinositide-3-kinase/v-akt murine thymoma viral oncogene homolog 1 pathways. These E2 rapid effects require a population of the ER alpha located at the cell plasma membrane through palmitoylation, a dynamic enzymatic modification mediated by palmitoyl-acyl-transferases. However, whether membrane-initiated and transcriptional ER alpha activities integrate in a unique picture or represent parallel pathways still remains to be firmly clarified. Hence, we evaluated here the impact of ER alpha palmitoylation on E2-induced ER alpha degradation and S118 phosphorylation. The lack of palmitoylation renders ER alpha more susceptible to E2-dependent degradation, blocks ER alpha S118 phosphorylation and prevents E2-induced ER alpha estrogen-responsive element-containing promoter occupancy. Consequently, ER alpha transcriptional activity is prevented and the receptor addressed to the nuclear matrix subnuclear compartment. These data uncover a circuitry in which receptor palmitoylation links E2-dependent ER alpha degradation, S118 phosphorylation, and transcriptional activity in a unique molecular mechanism. We propose that rapid E2-dependent signaling could be considered as a prerequisite for ER alpha transcriptional activity and suggest an integrated model of ER alpha intracellular signaling where E2-dependent early extranuclear effects control late receptor-dependent nuclear actions. (Molecular Endocrinology 26: 762-774, 2012)