Role of ERα Ufmylation in the control of estrogen signaling pathway

Abstract

UFM1, ubiquitin-like protein, is post-translationally conjugated to cellular proteins. The ufmylation reaction is catalyzed by an UFM1-activating E1 enzyme (UBA5), an UFM1-conjugating E2 enzyme (UBC1), and UFM1 E3 ligases (UFL1), in a manner similar to ubiquitination. Estrogen receptor α(ERα) is a member of a large conserved superfamily of steroid hormone nuclear receptors, acting as ligand-regulated transcription factor. ERα regulates many physiological pathways in response to its ligand, E2 (17β-estradiol). ERα is undergoing different types of post-translational modifications, such as phosphorylation, sumoylation, acetylation, and ubiquitination, which regulate its transcriptional activation and/or stability. Here, ERα was found to be a target for modification by UFM1. I also identified the major UFM1 acceptor site is in the AF1 domain. Moreover, knock down of UBA5 by RNA interference reduced the ERα transcriptional activity and accelerated E2-induced proteolysis. These results indicate that UFM1 modification plays a critical role in positive regulation of ERα function in transcriptional activation by preventing its degradation