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

Abstract

The estrogen receptor-α (ERα) is a transcription factor that regulates gene expression through the binding to its cognate hormone 17β-estradiol (E2). ERα transcriptional activity is regulated by E2-evoked 26S proteasome-mediated ERα degradation and ERα serine (S) residue 118 phosphorylation. Furthermore, ERα 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 ERα located at the cell plasma membrane through palmitoylation, a dynamic enzymatic modification mediated by palmitoyl-acyl-transferases. However, whether membrane-initiated and transcriptional ERα activities integrate in a unique picture or represent parallel pathways still remains to be firmly clarified. Hence, we evaluated here the impact of ERα palmitoylation on E2-induced ERα degradation and S118 phosphorylation. The lack of palmitoylation renders ERα more susceptible to E2-dependent degradation, blocks ERα S118 phosphorylation and prevents E2-induced ERα estrogen-responsive element-containing promoter occupancy. Consequently, ERα 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 ERα 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 ERα transcriptional activity and suggest an integrated model of ERα intracellular signaling where E2-dependent early extranuclear effects control late receptor-dependent nuclear actions.

Mutation of the palmitoylation site of estrogen receptor α in vivo reveals tissue-specific roles for membrane versus nuclear actions

“…S5D). Thus, although previous in vitro experiments suggested that ERα palmitoylation influences the abundance of the receptor protein (22), this was not detected in vivo in arteries and uterus.…”

“…We first determined whether mutation of the palmitoylation site of mouse ERα alters the expression level of the protein in vivo, because in vitro studies (22) had shown that such a mutated human ERα (C447A) was more sensitive to E2-dependent degradation. The mutated C451A-ERα protein was normal in abundance in the different murine tissues analyzed.…”

“…Previous cell culture studies indicated that disrupting the palmitoylation of ERα resulted in a receptor that is more sensitive to E2-dependent degradation (22). We therefore evaluated possible alterations in ER abundance, in presence of E2 treatment, in the arteries of C451A-ERα mice.…”

“…A nonpalmitoylatable Cys447Ala mutant form of ERα, or its C451A mutant mouse counterpart, expressed in cultured cells lacks interaction with caveolin-1 and downstream activation of signaling pathways and cell proliferation (18,19). Numerous cell culture experiments further suggest potentially important kinase-mediated cross-talk between membrane and nuclear ERα that modifies genomic responses to E2 (20,21), including recent studies revealing that MISS dependent on receptor palmitoylation influences receptor nuclear actions (22). Our current understanding of these processes has relied primarily on experimentation in cell culture.…”

Effets membranaires du récepteur alpha des œstrogènes

“…Par ailleurs, cette signalisation d'origine membranaire peut également moduler l'activité transcriptionelle d'ER via l'activation de kinases qui phosphorylent le récepteur nucléaire et modulent ainsi son activité nucléaire [34]. En ce qui concerne l'étude de la conformation de l'ER membranaire, la topologie du récepteur associé avec la membrane plasmique n'en est encore qu'à ses balbutiements.…”