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Journal Article

Hexosamine Pathway Activation Improves Protein Homeostasis through the Integrated Stress Response

MPS-Authors
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Horn,  M.
Denzel – Metabolic and Genetic Regulation of Ageing, Research Groups, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Denzel,  S. I.
Department Antebi - Molecular Genetics of Ageing, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Srinivasan,  B.
Denzel – Metabolic and Genetic Regulation of Ageing, Research Groups, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Allmeroth,  K.
Denzel – Metabolic and Genetic Regulation of Ageing, Research Groups, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Schiffer,  I.
Department Antebi - Molecular Genetics of Ageing, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Karthikaisamy,  V.
Denzel – Metabolic and Genetic Regulation of Ageing, Research Groups, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Miethe,  S.
Denzel – Metabolic and Genetic Regulation of Ageing, Research Groups, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Antebi,  A.
Department Antebi - Molecular Genetics of Ageing, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Denzel,  M. S.
Denzel – Metabolic and Genetic Regulation of Ageing, Research Groups, Max Planck Institute for Biology of Ageing, Max Planck Society;

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https://www.ncbi.nlm.nih.gov/pubmed/32086012
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Citation

Horn, M., Denzel, S. I., Srinivasan, B., Allmeroth, K., Schiffer, I., Karthikaisamy, V., et al. (2020). Hexosamine Pathway Activation Improves Protein Homeostasis through the Integrated Stress Response. iScience, 23(3), 100887. doi:10.1016/j.isci.2020.100887.


Cite as: https://hdl.handle.net/21.11116/0000-000B-3074-C
Abstract
Activation of the hexosamine pathway (HP) through gain-of-function mutations in its rate-limiting enzyme glutamine fructose-6-phosphate amidotransferase (GFAT-1) ameliorates proteotoxicity and increases lifespan in Caenorhabditis elegans. Here, we investigate the role of the HP in mammalian protein quality control. In mouse neuronal cells, elevation of HP activity led to phosphorylation of both PERK and eIF2alpha as well as downstream ATF4 activation, identifying the HP as a modulator of the integrated stress response (ISR). Increasing uridine 5'-diphospho-N-acetyl-D-glucosamine (UDP-GlcNAc) levels through GFAT1 gain-of-function mutations or supplementation with the precursor GlcNAc reduces aggregation of the polyglutamine (polyQ) protein Ataxin-3. Blocking PERK signaling or autophagy suppresses this effect. In C. elegans, overexpression of gfat-1 likewise activates the ISR. Consistently, co-overexpression of gfat-1 and proteotoxic polyQ peptides in muscles reveals a strong protective cell-autonomous role of the HP. Thus, the HP has a conserved role in improving protein quality control through modulation of the ISR.