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Glycosylation of KEAP1 links nutrient sensing to redox stress signaling.

Publication ,  Journal Article
Chen, P-H; Smith, TJ; Wu, J; Siesser, PF; Bisnett, BJ; Khan, F; Hogue, M; Soderblom, E; Tang, F; Marks, JR; Major, MB; Swarts, BM; Boyce, M; Chi, J-T
Published in: EMBO J
August 1, 2017

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.

Duke Scholars

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Published In

EMBO J

DOI

EISSN

1460-2075

Publication Date

August 1, 2017

Volume

36

Issue

15

Start / End Page

2233 / 2250

Location

England

Related Subject Headings

  • Stress, Physiological
  • Signal Transduction
  • Oxidation-Reduction
  • NF-E2-Related Factor 2
  • N-Acetylglucosaminyltransferases
  • Kelch-Like ECH-Associated Protein 1
  • Humans
  • Glycosylation
  • Gene Expression Regulation
  • Gene Expression Profiling
 

Citation

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MLA
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Chen, P.-H., Smith, T. J., Wu, J., Siesser, P. F., Bisnett, B. J., Khan, F., … Chi, J.-T. (2017). Glycosylation of KEAP1 links nutrient sensing to redox stress signaling. EMBO J, 36(15), 2233–2250. https://doi.org/10.15252/embj.201696113
Chen, Po-Han, Timothy J. Smith, Jianli Wu, Priscila F. Siesser, Brittany J. Bisnett, Farhan Khan, Maxwell Hogue, et al. “Glycosylation of KEAP1 links nutrient sensing to redox stress signaling.EMBO J 36, no. 15 (August 1, 2017): 2233–50. https://doi.org/10.15252/embj.201696113.
Chen P-H, Smith TJ, Wu J, Siesser PF, Bisnett BJ, Khan F, et al. Glycosylation of KEAP1 links nutrient sensing to redox stress signaling. EMBO J. 2017 Aug 1;36(15):2233–50.
Chen, Po-Han, et al. “Glycosylation of KEAP1 links nutrient sensing to redox stress signaling.EMBO J, vol. 36, no. 15, Aug. 2017, pp. 2233–50. Pubmed, doi:10.15252/embj.201696113.
Chen P-H, Smith TJ, Wu J, Siesser PF, Bisnett BJ, Khan F, Hogue M, Soderblom E, Tang F, Marks JR, Major MB, Swarts BM, Boyce M, Chi J-T. Glycosylation of KEAP1 links nutrient sensing to redox stress signaling. EMBO J. 2017 Aug 1;36(15):2233–2250.

Published In

EMBO J

DOI

EISSN

1460-2075

Publication Date

August 1, 2017

Volume

36

Issue

15

Start / End Page

2233 / 2250

Location

England

Related Subject Headings

  • Stress, Physiological
  • Signal Transduction
  • Oxidation-Reduction
  • NF-E2-Related Factor 2
  • N-Acetylglucosaminyltransferases
  • Kelch-Like ECH-Associated Protein 1
  • Humans
  • Glycosylation
  • Gene Expression Regulation
  • Gene Expression Profiling