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.
authors.affiliation: Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Zhao V
authors.initials: ZV
authors.lastname: Wang
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Yingfeng
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ningguo
authors.initials: N
authors.lastname: Gao
authors.affiliation: Department 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.
authors.forename: Zully
authors.initials: Z
authors.lastname: Pedrozo
authors.affiliation: Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Dan L
authors.initials: DL
authors.lastname: Li
authors.affiliation: Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Cyndi R
authors.initials: CR
authors.lastname: Morales
authors.affiliation: Department 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.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Criollo
authors.affiliation: Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Tan
authors.affiliation: Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lehrman
authors.affiliation: Department 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.
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Rothermel
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Ann-Hwee
authors.initials: AH
authors.lastname: Lee
authors.affiliation: Department 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.
authors.forename: Sergio
authors.initials: S
authors.lastname: Lavandero
authors.affiliation: Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Pradeep P A
authors.initials: PPA
authors.lastname: Mammen
authors.affiliation: Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Anwarul
authors.initials: A
authors.lastname: Ferdous
authors.affiliation: Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Gillette
authors.affiliation: Touchstone 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.
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.affiliation: Department 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.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
mesh_terms: D000818:Animals; D053898:Biosynthetic Pathways; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); D006595:Hexosamines / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D019884:Nitrogenous Group Transferases / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D056811:Unfolded Protein Response; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D006595:Hexosamines; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; D019884:Nitrogenous Group Transferases; C488523:Gfpt1 protein, mouse; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)