Glycosylation of KEAP1 links nutrient sensing to redox stress signaling.

Autor:	Chen PH; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.; Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA., Smith TJ; Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA., Wu J; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA., Siesser PF; Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Bisnett BJ; Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA., Khan F; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA., Hogue M; Department of Chemistry and Biochemistry, Central Michigan University, Mount Pleasant, MI, USA., Soderblom E; Duke Proteomics and Metabolomics Core Facility, Center for Genomic and Computational Biology, Duke University, Durham, NC, USA., Tang F; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA., Marks JR; Division of Surgical Sciences, Department of Surgery, Duke University, Durham, NC, USA., Major MB; Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Swarts BM; Department of Chemistry and Biochemistry, Central Michigan University, Mount Pleasant, MI, USA., Boyce M; Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA michael.boyce@duke.edu jentsan.chi@duke.edu., Chi JT; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA michael.boyce@duke.edu jentsan.chi@duke.edu.
Jazyk:	angličtina
Zdroj:	The EMBO journal [EMBO J] 2017 Aug 01; Vol. 36 (15), pp. 2233-2250. Date of Electronic Publication: 2017 Jun 29.
DOI:	10.15252/embj.201696113
Abstrakt:	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. (© 2017 The Authors.)
Databáze:	MEDLINE
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