GREB1: An evolutionarily conserved protein with a glycosyltransferase domain links ERα glycosylation and stability to cancer

What covalent modifications control the temporal ubiquitination of ER alpha and hence the duration of its transcriptional activity remain poorly understood. We show that GREB1, an ER alpha-inducible enzyme, catalyzes O-GlcNAcylation of ER alpha at residues T553/S554, which stabilizes ER alpha protein by inhibiting association with the ubiquitin ligase ZNF598. Loss of GREB1-mediated glycosylation of ER alpha results in reduced cellular ER alpha levels and insensitivity to estrogen. Higher GREB1 expression in ER alpha(+ve) breast cancer is associated with greater survival in response to tamoxifen, an ER alpha agonist. Mice lacking Greb1 exhibit growth and fertility defects reminiscent of phenotypes in ER alpha-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 ER alpha as its first substrate.

Automated summary

GREB1 catalyzes O-GlcNAcylation of ER alpha at residues T553/S554, stabilizing ER alpha protein by inhibiting its association with the ubiquitin ligase ZNF598. Loss of GREB1-mediated glycosylation of ER alpha results in reduced cellular ER alpha levels and insensitivity to estrogen, while higher GREB1 expression in ER alpha(+) breast cancer is associated with greater survival in response to tamoxifen.