Shin EM, Huynh VT, Neja SA, Liu CY, Raju A, Tan K, Tan NS, Gunaratne J, Bi X, Iyer LM, Aravind L, Tergaonkar V

What covalent modifications control the temporal ubiquitination of ER? and hence the duration of its transcriptional activity remain poorly understood. We show that GREB1, an ER?-inducible enzyme, catalyzes O-GlcNAcylation of ER? at residues T553/S554, which stabilizes ER? protein by inhibiting association with the ubiquitin ligase ZNF598. Loss of GREB1-mediated glycosylation ...

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of ER? results in reduced cellular ER? levels and insensitivity to estrogen. Higher GREB1 expression in ER?+ve breast cancer is associated with greater survival in response to tamoxifen, an ER? agonist. Mice lacking Greb1 exhibit growth and fertility defects reminiscent of phenotypes in ER?-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? as its first substrate.

Date: Mar. 01, 2021

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