Abstract 261: Robust Cardioprotection Afforded by a Previously Unrecognized Link between the Unfolded Protein Response and the Hexosamine Biosynthetic Pathway
Background: The hexosamine biosynthetic pathway (HBP) generates UDP-GlcNAc (uridine diphosphate N-acetylglucosamine) for glycan synthesis and O-linked GlcNAc (O-GlcNAc) protein modifications. Despite the established role of the HBP in glucose metabolism and multiple diseases, regulation of the HBP remains largely undefined.
Methods & Results: Here, we show that spliced Xbp1 (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 activation of the HBP by means of Xbp1s-dependent transcription of genes coding for key, rate-limiting enzymes. We establish that this previously unrecognized UPR-HBP axis is triggered in a variety of stress conditions known to promote O-GlcNAc modification. We go on to demonstrate that Xbp1s, acutely stimulated by ischemia/reperfusion (I/R) in heart, confers robust cardioprotection against I/R injury. We also show that HBP induction is required for this cardioprotective response. Mechanistically, HBP may mediate the adaptive branch of the UPR by activating autophagy and ER-associated degradation.
Conclusion: These studies reveal that Xbp1s couples the UPR to the HBP, promoting robust cardioprotection during I/R.
Author Disclosures: Z.V. Wang: None Y. Deng: None N. Gao: None Z. Pedrozo: None D. Li: None C. Morales: None A. Criollo: None X. Luo: None W. Tan: None N. Jiang: None M. Lehrman: None B. Rothermel: None A. Lee: None S. Lavandero: None P. Mammen: None A. Ferdous: None T. Gillette: None P. Scherer: None J. Hill: None.
This research has received full or partial funding support from the American Heart Association, National Center.
- © 2014 by American Heart Association, Inc.