Transcription factor Nrf1 is negatively regulated by its O‐GlcNAcylation status

Abstract

a b s t r a c tO-Linked N-acetylglucosamine transferase (OGT) was identified as an Nrf1-interacting protein.Herein, we show that Nrf1 enables interaction with OGT and their co-immunoprecipitates are O-GlcNAcylated by the enzyme. The putative O-GlcNAcylation negatively regulates Nrf1/TCF11 to reduce both its protein stability and transactivation activity of target gene expression. The turnover of Nrf1 is enhanced upon overexpression of OGT, which promotes ubiquitination of the CNC-bZIP protein. Furthermore, the serine/theorine-rich sequence of PEST2 degron within Nrf1 is identified to be involved in the protein O-GlcNAcylation by OGT. Overall, Nrf1 is negatively regulated by its O-GlcNAcylation status that depends on the glucose concentrations.

O-GlcNAcylation Signal Mediates Proteasome Inhibitor Resistance in Cancer Cells by Stabilizing NRF1

“…A previous study reported that NRF1 is O -GlcNAcylated and destabilized by this modification ( 46 ), which contrasts with our observation. One possible explanation of this discrepancy would be a different antibody used in each study.…”

TALENs-directed knockout of the full-length transcription factor Nrf1α that represses malignant behaviour of human hepatocellular carcinoma (HepG2) cells

“…3g ). Although similar proteins exhibited distinct electrophoretic mobility as reported previously 44 67 , western blotting results together with the genomic nucleotide sequencing revealed that knockout mutants in HB, HC, HD and HH cell lines are mono-allelic because a small fraction of Nrf1α-related proteins were retained, whilst other mutants in HA, HF, HG and HI cell lines are predicted to be heterozygous bi-allelic, but only HE mutant is homozygous bi-allelic with a very low level of Nrf1 mRNA being expressed ( Fig. 3d ).…”

Nuclear factor-erythroid-2 related transcription factor-1 (Nrf1) is regulated by O-GlcNAc transferase

“…While this manuscript was in preparation, another group reported that OGT negatively regulates expression of another Nrf1 isoform, TCF11 [70]. In their analysis, they observed that inhibition of OGT function by alloxan and siRNA-mediated knockdown led to increased TCF11 expression and function as measured by reporter gene activation.…”