title: 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.
authors.affiliation: Department of Biology, University Roma Tre, I-00146, Rome, Italy.
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: La Rosa
authors.forename: Valeria
authors.initials: V
authors.lastname: Pesiri
authors.forename: Guy
authors.initials: G
authors.lastname: Leclercq
authors.forename: Maria
authors.initials: M
authors.lastname: Marino
authors.forename: Filippo
authors.initials: F
authors.lastname: Acconcia
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors; D002402:Cathepsin D / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006801:Humans; D054878:Lipoylation / Q000187:drug effects*; D010168:Palmitates / Q000494:pharmacology; D019308:Palmitic Acid / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D053766:Presenilin-2 / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D059748:Proteolysis / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: C506487:ESR1 protein, human; D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D004967:Estrogens; C508861:PSEN2 protein, human; D010168:Palmitates; D053766:Presenilin-2; D012333:RNA, Messenger; C022776:2-bromopalmitate; D019308:Palmitic Acid; D012694:Serine; D004958:Estradiol; D000217:Acyltransferases; C105599:HHAT protein, human; C533922:CTSD protein, human; D002402:Cathepsin D