@article{93345c3c31094cfba10f345171a67fb3,
title = "Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway",
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.",
author = "Zhao Wang and Yingfeng Deng and Ningguo Gao and Zully Pedrozo and Li, {Dan L.} and Morales, {Cyndi R.} and Alfredo Criollo and Xiang Luo and Wei Tan and Nan Jiang and Lehrman, {Mark A} and Rothermel, {Beverly A} and Lee, {Ann Hwee} and Sergio Lavandero and Mammen, {Pradeep P} and Anwarul Ferdous and Gillette, {Thomas G.} and Scherer, {Philipp E} and Hill, {Joseph A}",
note = "Funding Information: We thank Herman May and Yongli Kong for technical assistance. We thank Dr. Gary Wright (Department of Pharmacology, Quillen College of Medicine, East Tennessee State University) for kindly providing equipment for the Langendorff experiments. This work was supported by grants from the National Institutes of Health (NIH) (HL-080144, HL-0980842, and HL-100401 to J.A.H.; DK-55758, DK-088761, and DK-099110 to P.E.S.; GM-038545 to M.A.L.; HL-102478-02 to P.P.A.M.; and HL-072016 and HL-097768 to B.A.R.), the Cancer Prevention Research Institute of Texas (CPRIT) (RP110486P3), the American Heart Association (AHA) DeHaan Foundation (0970518N), and the Fondation Leducq (11CVD04), and the Comision Nacional de Investigaci{\'o}n Cientifica y Tecnologica de Chile (FONDAP 15130011 to S.L., Z.P., and A.C.; Redes 120003 to S.L. and J.A.H.). Z.V.W. was supported by a postdoctoral fellowship from the AHA (10POST4320009). Y.D. was supported by a postdoctoral fellowship from the American Diabetes Association (ADA) (7-08-MN-53). Z.P. was supported by a postdoctoral fellowship from the Fondo Nacional de Desarrollo Cient{\'i}fico y Tecnol{\'o}gico, FONDECYT (3110039). A.C. was supported by The PEW Latin American Fellows Program in Biomedical Science. ",
year = "2014",
month = mar,
day = "13",
doi = "10.1016/j.cell.2014.01.014",
language = "English (US)",
volume = "156",
pages = "1179--1192",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "6",
}