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

Zhao Wang, Yingfeng Deng, Ningguo Gao, Zully Pedrozo, Dan L. Li, Cyndi R. Morales, Alfredo Criollo, Xiang Luo, Wei Tan, Nan Jiang, Mark A Lehrman, Beverly A Rothermel, Ann Hwee Lee, Sergio Lavandero, Pradeep P Mammen, Anwarul Ferdous, Thomas G. Gillette, Philipp E Scherer, Joseph A Hill

Research output: Contribution to journalArticlepeer-review

158 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1179-1192
Number of pages14
JournalCell
Volume156
Issue number6
DOIs
StatePublished - Mar 13 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway'. Together they form a unique fingerprint.

Cite this