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EMBO J. 2017 Aug 1;36(15):2233-2250. doi: 10.15252/embj.201696113. Epub 2017 Jun 29.

Glycosylation of KEAP1 links nutrient sensing to redox stress signaling.

Author information

1
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.
2
Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA.
3
Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
4
Department of Chemistry and Biochemistry, Central Michigan University, Mount Pleasant, MI, USA.
5
Duke Proteomics and Metabolomics Core Facility, Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.
6
Division of Surgical Sciences, Department of Surgery, Duke University, Durham, NC, USA.
7
Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA michael.boyce@duke.edu jentsan.chi@duke.edu.
8
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA michael.boyce@duke.edu jentsan.chi@duke.edu.

Abstract

O-GlcNAcylation is an essential, nutrient-sensitive post-translational modification, but its biochemical and phenotypic effects remain incompletely understood. To address this question, we investigated the global transcriptional response to perturbations in O-GlcNAcylation. Unexpectedly, many transcriptional effects of O-GlcNAc transferase (OGT) inhibition were due to the activation of NRF2, the master regulator of redox stress tolerance. Moreover, we found that a signature of low OGT activity strongly correlates with NRF2 activation in multiple tumor expression datasets. Guided by this information, we identified KEAP1 (also known as KLHL19), the primary negative regulator of NRF2, as a direct substrate of OGT We show that O-GlcNAcylation of KEAP1 at serine 104 is required for the efficient ubiquitination and degradation of NRF2. Interestingly, O-GlcNAc levels and NRF2 activation co-vary in response to glucose fluctuations, indicating that KEAP1 O-GlcNAcylation links nutrient sensing to downstream stress resistance. Our results reveal a novel regulatory connection between nutrient-sensitive glycosylation and NRF2 signaling and provide a blueprint for future approaches to discover functionally important O-GlcNAcylation events on other KLHL family proteins in various experimental and disease contexts.

KEYWORDS:

KLHL ; OGT ; KEAP1; NRF2; O‐GlcNAcylation

PMID:
28663241
PMCID:
PMC5538768
DOI:
10.15252/embj.201696113
[Indexed for MEDLINE]
Free PMC Article

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