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Cell. 2014 Mar 13;156(6):1179-92. doi: 10.1016/j.cell.2014.01.014.

Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway.

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  • 1Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 3Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 4Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Advanced Center for Chronic Diseases (ACCDiS) and Centro Estudios Moleculares de la Celula, Facultad Ciencias Quimicas y Farmaceuticas and Facultad Medicina, Universidad de Chile, Santiago, Chile; Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile.
  • 5Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Advanced Center for Chronic Diseases (ACCDiS) and Centro Estudios Moleculares de la Celula, Facultad Ciencias Quimicas y Farmaceuticas and Facultad Medicina, Universidad de Chile, Santiago, Chile; Dental Science Research Institute, Facultad de Odontologia, Universidad de Chile, Santiago, Chile.
  • 6Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 7Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
  • 8Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 9Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: joseph.hill@utsouthwestern.edu.

Abstract

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.

Copyright © 2014 Elsevier Inc. All rights reserved.

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