Spliced X-Box Binding Protein 1 Couples the Unfolded Protein Response to Hexosamine Biosynthetic Pathway
2014
Wang, Zhao V. | Deng, Yingfeng | Gao, Ningguo | Pedrozo, Zully | Li, Dan L. | Morales, Cyndi R. | Criollo, Alfredo | Luo, Xiang | Tan, Wei | Jiang, Nan | Lehrman, Mark A. | Rothermel, Beverly A. | Lee, Ann-Hwee | Lavandero, Sergio | Mammen, Pradeep P.A. | Ferdous, Anwarul | Gillette, Thomas G. | Scherer, Philipp E. | Hill, Joseph A.
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.
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