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

Cell. 2014 Mar 13;156(6):1179-1192. doi: 10.1016/j.cell.2014.01.014.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biosynthetic Pathways*
  • DNA-Binding Proteins / metabolism*
  • Hexosamines / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Myocardial Ischemia / metabolism
  • Myocardial Reperfusion Injury / metabolism
  • Myocytes, Cardiac / metabolism
  • Nitrogenous Group Transferases / genetics
  • Regulatory Factor X Transcription Factors
  • Transcription Factors / metabolism*
  • Unfolded Protein Response*
  • X-Box Binding Protein 1

Substances

  • DNA-Binding Proteins
  • Hexosamines
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Xbp1 protein, mouse
  • Nitrogenous Group Transferases
  • Gfpt1 protein, mouse