Editors' ChoiceCell Biology

Preventing Stress with Sugar

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Sci. Signal.  01 Apr 2014:
Vol. 7, Issue 319, pp. ec83
DOI: 10.1126/scisignal.2005319

Endoplasmic reticulum (ER) dysfunction stimulates the unfolded protein response, which includes transcriptional activation of genes encoding ER stress-response proteins by the active splice-isoform of the DNA-binding protein x-box binding protein 1 (XBP1s). Among other roles, N-linked glycosylation of proteins in the ER is required for proper folding, whereas O-linked glycosylation of nuclear and cytosolic proteins modifies their function. The hexosamine biosynthetic pathway converts glucose to uradine diphosphate-N-acetyl-glucosamine (UDP-GlcNAc), a precursor for both N- and O-linked glycosylation. In a mouse model of ischemia-reperfusion–induced cardiac injury, Wang et al. discovered that reperfused hearts had increased O-GlcNAc modification of proteins, as well as increased abundance of Xbp1s, ER stress-response chaperone proteins, and enzymes in the hexosamine pathway. The promoter of several genes encoding hexosamine pathway enzymes contained Xbp1s-binding sites, and overexpressed Xbp1s bound to and increased the expression of GFAT1, which encodes a rate-limiting hexosamine pathway enzyme. Heart-specific overexpression of Xbp1s in mice increased free UDP-GlcNAc abundance and O-GlcNAc modification of proteins, whereas silencing Xbp1s in the heart exacerbated ischemia-reperfusion–induced injury. Inhibition of GFAT1 prevented the cardioprotective effects of Xbp1s overexpression in both ex vivo heart and cultured myocyte ischemia-reperfusion models, whereas application of exogenous UDP-GlcNAc or overexpression of GFAT1 reduced ischemia-reperfusion–induced cell death in cultured myocytes with Xbp1s knockdown. Thus, the hexosamine pathway acts downstream of the unfolded protein response to limit cardiac injury due to ischemia reperfusion. Aging is associated with cellular stress, including the disruption of ER homeostasis. Denzel et al. identified three alleles of gfat1 in Caenorhabditis elegans that conferred resistance to tunicamycin exposure, which inhibits N-linked glycosylation and causes ER stress and death. Genetic and siRNA analyses indicated that these alleles produced dominant gain-of-function mutations, and gfat1-overexpressing worms also resisted tunicamycin-induced lethality. gfat1 mutant worms had increased abundance of free UDP-HexNAcs (a pool of UDP-GlcNAc and UDP-N-acetyl-galactosamine), and supplying worms with exogenous GlcNAc or UDP-GlcNAc inhibited tunicamycin-induced lethality. Worms given exogenous GlcNAc or with gfat1 mutations had reduced aggregation of overexpressed mutant proteins that misfold in the ER. Worms with gfat1 mutations or overexpressing gfat1, or those given moderate amounts of exogenous GlcNAc lived longer in the absence of tunicamycin. This effect was independent of other longevity pathways, such as the FOXO-pathway, which also responds to cellular stress, but depended on the unfolded protein response–associated genes xbp1 and ire1. Knockdown of xbp1 or ire1 inhibited the ability of gfat1 mutations to prevent misfolded protein aggregation. In addition, gfat1 mutations or exogenous GlcNAc increased expression of genes encoding proteins involved in ER-assisted protein degradation (ERAD), another pathway involved in the ER stress response. Knockdown of ERAD-associated genes also inhibited the ability of gfat1 mutations to increase longevity. Thus, crosstalk between ER stress and hexosamine biosynthesis suggests that there may be therapeutic applications for hexosamine metabolites in degenerative diseases (see Vincenz and Hartl).

M. S. Denzel, N. J. Storm, A. Gutschmidt, R. Baddi, Y. Hinze, E. Jarosch, T. Sommer, T. Hoppe, A. Antebi, Hexosamine pathway metabolites enhance protein quality control and prolong life. Cell 156, 1167–1178 (2014). [PubMed]

Z. V. Wang, Y. Deng, N. Gao, Z. Pedrozo, D. L. Li, C. R. Morales, A. Criollo, X. Luo, W. Tan, N. Jiang, M. A. Lehrman, B. A. Rothermel, A.-H. Lee, S. Lavandero, P. P. A. Mammen, A. Ferdous, T. G. Gillette, P. E. Scherer, J. A. Hill, Spliced x-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway. Cell 156, 1179–1192 (2014). [PubMed]

L. Vincenz, F. U. Hartl, Sugarcoating ER stress. Cell 156, 1125–1127 (2014). [PubMed]