title: Lysosomal function is involved in 17β-estradiol-induced estrogen receptor α degradation and cell proliferation.
abstract: The homeostatic control of the cellular proteome steady-state is dependent either on the 26S proteasome activity or on the lysosome function. The sex hormone 17β-estradiol (E2) controls a plethora of biological functions by binding to the estrogen receptor α (ERα), which is both a nuclear ligand-activated transcription factor and also an extrinsic plasma membrane receptor. Regulation of E2-induced physiological functions (e.g., cell proliferation) requires the synergistic activation of both transcription of estrogen responsive element (ERE)-containing genes and rapid extra-nuclear phosphorylation of many different signalling kinases (e.g., ERK/MAPK; PI3K/AKT). Although E2 controls ERα intracellular content and activity via the 26S proteasome-mediated degradation, biochemical and microscopy-based evidence suggests a possible cross-talk among lysosomes and ERα activities. Here, we studied the putative localization of endogenous ERα to lysosomes and the role played by lysosomal function in ERα signalling. By using confocal microscopy and biochemical assays, we report that ERα localizes to lysosomes and to endosomes in an E2-dependent manner. Moreover, the inhibition of lysosomal function obtained by chloroquine demonstrates that, in addition to 26S proteasome-mediated receptor elimination, lysosome-based degradation also contributes to the E2-dependent ERα breakdown. Remarkably, the lysosome function is further involved in those ERα activities required for E2-dependent cell proliferation while it is dispensable for ERα-mediated ERE-containing gene transcription. Our discoveries reveal a novel lysosome-dependent degradation pathway for ERα and show a novel biological mechanism by which E2 regulates ERα cellular content and, as a consequence, cellular functions.
authors.affiliation: Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Rome, Italy.
authors.forename: Pierangela
authors.initials: P
authors.lastname: Totta
authors.affiliation: Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Rome, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Pesiri
authors.affiliation: Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Marino
authors.affiliation: Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Rome, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Acconcia
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D061986:MCF-7 Cells; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D021381:Protein Transport; D059748:Proteolysis / Q000187:drug effects; D015398:Signal Transduction
chemical_list: D047628:Estrogen Receptor alpha; D004958:Estradiol; D046988:Proteasome Endopeptidase Complex
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