Journal
CELL
Volume 156, Issue 6, Pages 1179-1192Publisher
CELL PRESS
DOI: 10.1016/j.cell.2014.01.014
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Funding
- National Institutes of Health (NIH) [HL-080144, HL-0980842, HL-100401, DK-55758, DK-088761, DK-099110, GM-038545, HL-102478-02, HL-072016, HL-097768]
- Cancer Prevention Research Institute of Texas (CPRIT) [RP110486P3]
- American Heart Association (AHA) DeHaan Foundation [0970518N]
- Fondation Leducq [11CVD04]
- Comision Nacional de Investigacion Cientifica y Tecnologica de Chile [FONDAP 15130011, Redes 120003]
- AHA [10POST4320009]
- American Diabetes Association (ADA) [7-08-MN-53]
- Fondo Nacional de Desarrollo Cientifico y Tecnologico, FONDECYT [3110039]
- PEW Latin American Fellows Program in Biomedical Science
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The hexosamine biosynthetic pathway (HBP) generates uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) for glycan synthesis and O-linked GlcNAc (O-GlcNAc) protein modifications. Despite the established role of the HBP in metabolism and multiple diseases, regulation of the HBP remains largely undefined. Here, we show that spliced X-box binding protein 1 (Xbp1s), the most conserved signal transducer of the unfolded protein response (UPR), is a direct transcriptional activator of the HBP. We demonstrate that the UPR triggers HBP activation via Xbp1s-dependent transcription of genes coding for key, rate-limiting enzymes. We further establish that this previously unrecognized UPR-HBP axis is triggered in a variety of stress conditions. Finally, we demonstrate a physiologic role for the UPR-HBP axis by showing that acute stimulation of Xbp1s in heart by ischemia/reperfusion confers robust cardioprotection in part through induction of the HBP. Collectively, these studies reveal that Xbp1s couples the UPR to the HBP to protect cells under stress.
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