title: A dynamic network of estrogen receptors in murine lymphocytes: fine-tuning the immune response.
abstract: The actual level of circulating estrogen (17β-estradiol, E2) has a serious impact on regulation of diverse immune cell functions, where their classical cytoplasmic receptors, ERα and ERβ, act as nuclear transcriptional regulators of multiple target genes. There is growing evidence, however, for rapid, "non-nuclear" regulatory effects of E2 on lymphocytes. Such effects are likely mediated by putative membrane-associated receptor(s) (mER), but the mechanistic details and the involved signaling pathways still remained largely unknown because of their complexity. Here, we show that in lymphocytes, mERs can signalize themselves, and upon ligation, they are able to coordinate translocation of other E2Rs to the PM. Our data firmly imply existence of a complex, dynamic network of at least seven ER forms in murine lymphocytes: cytoplasmic and membrane-linked forms of ERα, ERβ, or GPR30 and a mER that can receive extracellular E2 signals. The latter mERs are likely palmitoylated, as they are enriched in lipid-raft microdomains, and their E2 binding is also cholesterol dependent. The data also support that ligation of mERs can induce rapid regulatory signals to lymphocytes and then internalize and let the E2 liberate in lysosomes. In addition, they can dynamically control the cell-surface linkage of other cytoplasmic ERs. As demonstrated by the differential effects of mER or cytoplasmic ER ligation on the proliferation of activated T and B lymphocytes, such a dynamic E2R network can be considered as a tool to manage accommodation/fine-tuning of lymphocytes to rapidly changing hormone levels.
authors: Department of Immunology, Institute of Biology, Eotvos Lorand University, Budapest, Hungary; and.
authors: Andrea E
authors: AE
authors: Schneider
authors: Department of Immunology, Institute of Biology, Eotvos Lorand University, Budapest, Hungary; and.
authors: Eva
authors: E
authors: Kárpáti
authors: Department of Immunology, Institute of Biology, Eotvos Lorand University, Budapest, Hungary; and.
authors: Kitti
authors: K
authors: Schuszter
authors: Department of Immunology, Institute of Biology, Eotvos Lorand University, Budapest, Hungary; and.
authors: Eszter A
authors: EA
authors: Tóth
authors: Department of Immunology, Institute of Biology, Eotvos Lorand University, Budapest, Hungary; and.
authors: Endre
authors: E
authors: Kiss
authors: Department of Obstetrics and Reproduction, Faculty of Veterinary Science, Szent Istvan University, Budapest, Hungary.
authors: Margit
authors: M
authors: Kulcsár
authors: Department of Immunology, Institute of Biology, Eotvos Lorand University, Budapest, Hungary; and.
authors: Glória
authors: G
authors: László
authors: Department of Immunology, Institute of Biology, Eotvos Lorand University, Budapest, Hungary; and matko@elte.hu.
authors: Janos
authors: J
authors: Matko
mesh_terms: D000818:Animals; D000917:Antibody Formation; D002462:Cell Membrane / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D030762:Estrous Cycle; D005260:Female; D015870:Gene Expression; D006728:Hormones / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D011485:Protein Binding; D060066:Protein Interaction Maps; D021381:Protein Transport; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C532507:GPER1 protein, mouse; D006728:Hormones; D008024:Ligands; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D004958:Estradiol
keywords: lipid rafts; lymphocyte plasma membrane; lymphoid expression pattern; signal transduction; translocation