Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research, Singapore 138673, Singapore.
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
Sci Adv. 2021 Mar 17;7(12). doi: 10.1126/sciadv.abe2470. Print 2021 Mar.
What covalent modifications control the temporal ubiquitination of ERα and hence the duration of its transcriptional activity remain poorly understood. We show that GREB1, an ERα-inducible enzyme, catalyzes O-GlcNAcylation of ERα at residues T553/S554, which stabilizes ERα protein by inhibiting association with the ubiquitin ligase ZNF598. Loss of GREB1-mediated glycosylation of ERα results in reduced cellular ERα levels and insensitivity to estrogen. Higher expression in ERα breast cancer is associated with greater survival in response to tamoxifen, an ERα agonist. Mice lacking exhibit growth and fertility defects reminiscent of phenotypes in ERα-null mice. In summary, this study identifies GREB1, a protein with an evolutionarily conserved domain related to DNA-modifying glycosyltransferases of bacteriophages and kinetoplastids, as the first inducible and the only other (apart from OGT) O-GlcNAc glycosyltransferase in mammalian cytoplasm and ERα as its first substrate.
什么共价修饰控制 ERα 的时间性泛素化，从而控制其转录活性的持续时间，目前仍知之甚少。我们表明，GREB1 是一种 ERα 诱导的酶，可催化 ERα 在 T553/S554 残基上的 O-GlcNAc 化，通过抑制与泛素连接酶 ZNF598 的结合来稳定 ERα 蛋白。GREB1 介导的 ERα 糖基化的丧失导致细胞内 ERα 水平降低，并对雌激素不敏感。在 ERα 乳腺癌中表达水平较高与对他莫昔芬（一种 ERα 激动剂）治疗的反应性更好的生存相关。缺乏 GREB1 的小鼠表现出生长和生育缺陷，类似于 ERα 缺失小鼠的表型。总之，这项研究确定了 GREB1，一种与噬菌体和动基体 DNA 修饰糖苷转移酶具有进化保守结构域相关的蛋白质，是哺乳动物细胞质和 ERα 中第一个可诱导的，也是唯一的（除了 OGT 之外） O-GlcNAc 糖基转移酶，而 ERα 是其第一个底物。
