Lysosomal Function Is Involved in 17β-Estradiol-Induced Estrogen Receptor α Degradation and Cell Proliferation

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 beta-estradiol (E2) controls a plethora of biological functions by binding to the estrogen receptor alpha (ER alpha), 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 alpha intracellular content and activity via the 26S proteasome-mediated degradation, biochemical and microscopy-based evidence suggests a possible cross-talk among lysosomes and ERa activities. Here, we studied the putative localization of endogenous ERa to lysosomes and the role played by lysosomal function in ERa signalling. By using confocal microscopy and biochemical assays, we report that ER alpha 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 ERa breakdown. Remarkably, the lysosome function is further involved in those ERa activities required for E2-dependent cell proliferation while it is dispensable for ER alpha-mediated ERE-containing gene transcription. Our discoveries reveal a novel lysosome-dependent degradation pathway for ER alpha and show a novel biological mechanism by which E2 regulates ER alpha cellular content and, as a consequence, cellular functions.