Endocrine Abstracts

Protein ubiquitination modulates many physiological processes (e.g. cell proliferation). The ubiquitin-based signalling consists in both proteolytic and non-proteolytic functions: the first ones require modification of the target protein with polyubiquitination, a modification that induces the activation of the 26S-proteasome, whereas the second ones can be based on protein monoubiquitination. The recognition of ubiquitination diversity is dependent on specific Ub receptors that bind to the ubiquitinated protein by contacting the Ub-modification through specific ubiquitin-binding domains (UBDs).

Estrogen receptor α (ERα) is a ligand-activated nuclear receptor that mediates the cellular effects of the steroid hormone 17β-estradiol (E₂). The ERα-based signalling is a function of receptor intracellular localization. While ERα nuclear localization is required for E₂-induced gene transcription, the ERα extra-nuclear localization is necessary to trigger the rapid activation of several signalling kinase cascades (e.g. ERK/MAPK, PI3K/AKT).

Recent data provided the initial evidence that proteolytic and non-proteolytic Ub-based functions modulate ERα activities. ERα is a monoubiquitinated protein but the monoubiquitination-dependent regulation of the ERα activities that lead to the activation of cell proliferation are not known. Furthermore, the fact that ERα is a monoubiquitinated protein opens the possibility that an UBD could be present within the ERα structure and that the receptor could behave as an ubiquitin receptor. However, whether non-covalent Ub: ERα binding could occur and play a role in E₂: ERα signalling is unknown.

Here, we show that mutation of the ERα monoubiquitination sites prevents the E₂: ERα-mediated activation of signalling pathways to cell proliferation. In addition, a previously unrecognized Ub-binding surface has been found within the ERα and contribute to the E₂ transcriptional activity.

Altogether, these data indicate that the ERα belongs to the Ub-based signalling network and that receptor monoubiquitination as well as non-covalent Ub binding regulate ERα functions in a non-proteolytic manner.