Journal
JOURNAL OF CELL SCIENCE
Volume 126, Issue 12, Pages 2577-2582Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.123307
Keywords
17 beta-estradiol; Estrogen receptor; Ubiquitin; Ubiquitin binding domains; Signal transduction
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Funding
- Associazione Italiana Ricerca sul Cancro (AIRC) [MFAG12756]
- Ateneo Roma Tre
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Ubiquitin (Ub)-binding domains (UBDs) located in Ub receptors decode the ubiquitination signal by non-covalently engaging the Ub modification on their binding partners and transduce the Ub signalling through Ub-based molecular interactions. In this way, inducible protein ubiquitination regulates diverse biological processes. The estrogen receptor alpha (ER alpha) is a ligand-activated transcription factor that mediates the pleiotropic effects of the sex hormone 17 beta-estradiol (E2). Fine regulation of E2 pleiotropic actions depends on E2-dependent ER alpha association with a plethora of binding partners and/or on the E2 modulation of receptor ubiquitination. Indeed, E2-induced ER alpha polyubiquitination triggers receptor degradation and transcriptional activity, and E2-dependent reduction in ER alpha monoubiquitination is crucial for E2 signalling. Monoubiquitinated proteins often contain UBDs, but whether non-covalent Ub-ER alpha binding could occur and play a role in E2-ER alpha signalling is unknown. Here, we report an Ub-binding surface within the ER alpha ligand binding domain that directs in vitro the receptor interaction with both ubiquitinated proteins and recombinant Ub chains. Mutational analysis reveals that ER alpha residues leucine 429 and alanine 430 are involved in Ub binding. Moreover, impairment of ER alpha association to ubiquitinated species strongly affects E2-induced ER alpha transcriptional activity. Considering the importance of UBDs in the Ub-based signalling network and the central role of different ER alpha binding partners in the modulation of E2-dependent effects, our discoveries provide novel insights into ER alpha activity that could also be relevant for ER alpha-dependent diseases.
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