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Activation of the Transcriptional Function of the NF-κB Protein c-Rel by O-GlcNAc Glycosylation

Ramakrishnan, Parameswaran and Clark, Peter M. and Mason, Daniel E. and Peters, Eric C. and Hsieh-Wilson, Linda C. and Baltimore, David (2013) Activation of the Transcriptional Function of the NF-κB Protein c-Rel by O-GlcNAc Glycosylation. Science Signaling, 6 (290). Art. No. ra75. ISSN 1937-9145. PMCID PMC4066889. doi:10.1126/scisignal.2004097.

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The transcription factor nuclear factor κB (NF-κB) rapidly reprograms gene expression in response to various stimuli, and its activity is regulated by several posttranslational modifications, including phosphorylation, methylation, and acetylation. The addition of O-linked b-N-acetylglucosamine (a process known as O-GlcNAcylation) is an abundant posttranslational modification that is enhanced in conditions such as hyperglycemia and cellular stress. We report that the NF-κB subunit c-Rel is modified and activated by O-GlcNAcylation. We identified serine 350 as the site of O-GlcNAcylation, which was required for the DNA binding and transactivation functions of c-Rel. Blocking the O-GlcNAcylation of this residue abrogated c-Rel–mediated expression of the cytokine-encoding genes IL2, IFNG, and CSF2 in response to T cell receptor (TCR) activation, whereas increasing the extent of O-GlcNAcylation of cellular proteins enhanced the expression of these genes. TCR- or tumor necrosis factor (TNF)–induced expression of other NF-κB target genes, such as NFKBIA (which encodes IkBa) and TNFAIP3 (which encodes A20), occurred independently of the O-GlcNAcylation of c-Rel. Our findings suggest a stimulus-specific role for hyperglycemia-induced O-GlcNAcylation of c-Rel in promoting T cell–mediated autoimmunity in conditions such as type 1 diabetes by enhancing the production of T helper cell cytokines.

Item Type:Article
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URLURL TypeDescription DOIArticle;6/290/ra75?view=abstractPublisherArticle CentralArticle
Ramakrishnan, Parameswaran0000-0002-1314-827X
Hsieh-Wilson, Linda C.0000-0001-5661-1714
Baltimore, David0000-0001-8723-8190
Additional Information:© 2013 American Association for the Advancement of Science. Submitted 22 February 2013; Accepted 9 August 2013; Final Publication 27 August 2013. We express our deep and sincere gratitude to the late N. Sharon for invaluable advice and discussions. We thank A. Weiss for the CD28RE luciferase reporter plasmid; A. Balazs for the lentiviral expression plasmids; the Caltech animal facility; the Caltech protein expression center for baculoviral expression; and J. Rexach, R. Parameswaran, C.-K. Ea, L. Yang, and other members of the Baltimore laboratory for insightful discussions. Funding: This work was initially supported by NIH grant 2R01 GM039458 to D.B., 2RO1 GM084724 to L.C.H.-W., and later by a Mizutani Foundation for Glycoscience grant to P.R. Author contributions: P.R. conceived the project and designed and performed the experiments; P.M.C. performed the PEG labeling; D.E.M. and E.C.P. performed the mass spectrometry; P.R., P.M.C., L.C.H.-W., and D.B. analyzed and interpreted the data; and P.R. and D.B. wrote, and all of the authors edited, the manuscript. Competing interests: A patent was filed for the targeting of c-Rel O-GlcNAcylation (File No. CIT-6437-P).
Funding AgencyGrant Number
NIH2R01 GM039458
NIH2RO1 GM084724
Mizutani Foundation for GlycoscienceUNSPECIFIED
Issue or Number:290
PubMed Central ID:PMC4066889
Record Number:CaltechAUTHORS:20130919-142521151
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Official Citation:P. Ramakrishnan, P. M. Clark, D. E. Mason, E. C. Peters, L. C. Hsieh-Wilson, D. Baltimore, Activation of the transcriptional function of the NF-kB protein c-Rel by O-GlcNAc glycosylation. Sci. Signal. 6, ra75 (2013)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:41422
Deposited By: Tony Diaz
Deposited On:19 Sep 2013 21:53
Last Modified:10 Nov 2021 04:29

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