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Glycosylation of <scp>KEAP</scp> 1 links nutrient sensing to redox stress signaling
- Source :
- The EMBO Journal. 36:2233-2250
- Publication Year :
- 2017
- Publisher :
- EMBO, 2017.
-
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.
- Subjects :
- 0301 basic medicine
Glycosylation
NF-E2-Related Factor 2
Nutrient sensing
Biology
N-Acetylglucosaminyltransferases
environment and public health
General Biochemistry, Genetics and Molecular Biology
Cell Line
Serine
03 medical and health sciences
chemistry.chemical_compound
Ubiquitin
Stress, Physiological
Humans
Molecular Biology
Regulation of gene expression
Kelch-Like ECH-Associated Protein 1
General Immunology and Microbiology
Gene Expression Profiling
General Neuroscience
Articles
respiratory system
KEAP1
Cell biology
Gene expression profiling
030104 developmental biology
Gene Expression Regulation
Biochemistry
chemistry
Food
biology.protein
Signal transduction
Oxidation-Reduction
Signal Transduction
Subjects
Details
- ISSN :
- 14602075 and 02614189
- Volume :
- 36
- Database :
- OpenAIRE
- Journal :
- The EMBO Journal
- Accession number :
- edsair.doi.dedup.....3c2ada5aecd451b0fd5ec3705bfabd48