Proteasome-dependent degradation of the human estrogen receptor

TLDR

The ubiquitin–proteasome system is the primary pathway for rapid degradation of short‑lived proteins in eukaryotic cells, with ubiquitin attachment marking proteins for proteasomal recognition and destruction. We show that estradiol induces rapid degradation of the human estrogen receptor via the ubiquitin–proteasome pathway, a process that requires UBA/UBC enzymes and is blocked by proteasome inhibitors MG132 and lactacystin, while these enzymes do not affect progesterone or thyroid hormone receptor β.

Abstract

In eukaryotic cells, the ubiquitin–proteasome pathway is the major mechanism for the targeted degradation of proteins with short half-lives. The covalent attachment of ubiquitin to lysine residues of targeted proteins is a signal for the recognition and rapid degradation by the proteasome, a large multi-subunit protease. In this report, we demonstrate that the human estrogen receptor (ER) protein is rapidly degraded in mammalian cells in an estradiol-dependent manner. The treatment of mammalian cells with the proteasome inhibitor MG132 inhibits activity of the proteasome and blocks ER degradation, suggesting that ER protein is turned over through the ubiquitin–proteasome pathway. In addition, we show that in vitro ER degradation depends on ubiquitin-activating E1 enzyme (UBA) and ubiquitin-conjugating E2 enzymes (UBCs), and the proteasome inhibitors MG132 and lactacystin block ER protein degradation in vitro . Furthermore, the UBA/UBCs and proteasome inhibitors promote the accumulation of higher molecular weight forms of ER. The UBA and UBCs, which promote ER degradation in vitro , have no significant effect on human progesterone receptor and human thyroid hormone receptor β proteins.