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Post-translational modification

Sweetening protein quality control

Nature Reviews Molecular Cell Biology volume 15, page 295 (2014)Cite this article

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The hexosamine biosynthetic pathway (HBP) produces the nucleotide sugar uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc). This metabolite is a substrate for N-glycosylation, a process important for protein folding within the endoplasmic reticulum (ER), and nutrient-driven O-GlcNAcylation. Two studies now report that activation of the HBP following ER stress promotes longevity and cardioprotection, and identify GFAT1 (glutamine fructose 6-phosphate aminotransferase 1), the rate-limiting enzyme of the HBP, as a central node that links the stress response to glucose metabolism and protein homeostasis.

In the second study, Denzel et al. screened for Caenorhabditis elegans mutants that were resistant to an inducer of ER stress. They found that animals carrying a gfat-1 gain-of-function mutation had increased endogenous UDP-GlcNAc levels and an extended lifespan, and they hypothesized that the observed lifespan extension was owing to improved ER protein quality control. Indeed, they found that toxic protein aggregation was decreased in the ER lumen both in mutant animals and following the addition of GlcNAc, which suggests that activity of the HBP improves the clearance of misfolded proteins. Although the authors did not detect UPR activation or changes in UPR-target genes, they showed that expression of SEL-1, a subunit of a ubiquitin ligase that is involved in ER-associated protein degradation (ERAD; a process whereby misfolded ER proteins are targeted for proteasomal degradation), was increased in mutant animals; knockdown of sel-1 augmented protein aggregation and abolished the longevity of gfat-1 gain-of-function mutants. In addition, gfat-1 mutants exhibited increased proteasomal activity, which indicates that improved ER protein homeostasis is linked to greater proteolytic capacity and longevity. Interestingly, the authors showed that another cellular degradation pathway, autophagy, was induced in mutant animals, which leads to an increased lifespan. Thus, activation of the HBP induces distinct quality control pathways to protect cells from the toxic aggregation of misfolded proteins.

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References

  1. Wang, Z. V. et al. Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway. Cell 156, 1179–1192 (2014)

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  2. Denzel, M. S. et al. Hexosamine pathway metabolites enhance protein quality control and prolong life. Cell 156, 1167–1178 (2014)

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  1. Andrea Du Toit
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Hetz, C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nature Rev. Mol. Cell Biol. 13, 89–102 (2012)

Moremen, K. W., Tiemeyer, M. & Nairn, A. V. Vertebrate protein glycosylation: diversity, synthesis and function. Nature Rev. Mol. Cell Biol. 13, 448–462 (2012)

Hanover, J. A., Krause, M. W. & Love, D. C. Bittersweet memories: linking metabolism to epigenetics through O-GlcNAcylation. Nature Rev. Mol. Cell Biol. 13, 312–321 (2012)

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Du Toit, A. Sweetening protein quality control. Nat Rev Mol Cell Biol 15, 295 (2014). https://doi.org/10.1038/nrm3787

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