%0 Journal Article
%T Lysosomal Function Is Involved in 17¦Â-Estradiol-Induced Estrogen Receptor ¦Á Degradation and Cell Proliferation
%A Pierangela Totta
%A Valeria Pesiri
%A Maria Marino
%A Filippo Acconcia
%J PLOS ONE
%D 2014
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0094880
%X 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 17¦Â-estradiol (E2) controls a plethora of biological functions by binding to the estrogen receptor ¦Á (ER¦Á), 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 ER¦Á intracellular content and activity via the 26S proteasome-mediated degradation, biochemical and microscopy-based evidence suggests a possible cross-talk among lysosomes and ER¦Á activities. Here, we studied the putative localization of endogenous ER¦Á to lysosomes and the role played by lysosomal function in ER¦Á signalling. By using confocal microscopy and biochemical assays, we report that ER¦Á 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 ER¦Á breakdown. Remarkably, the lysosome function is further involved in those ER¦Á activities required for E2-dependent cell proliferation while it is dispensable for ER¦Á-mediated ERE-containing gene transcription. Our discoveries reveal a novel lysosome-dependent degradation pathway for ER¦Á and show a novel biological mechanism by which E2 regulates ER¦Á cellular content and, as a consequence, cellular functions.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0094880