Hexosamine Pathway Activation Improves Protein Homeostasis through the Integrated Stress Response

• Published in: iScience Vol. 23; no. 3; p. 100887
• Main Authors: Horn, Moritz, Denzel, Sarah I., Srinivasan, Balaji, Allmeroth, Kira, Schiffer, Isabelle, Karthikaisamy, Vignesh, Miethe, Stephan, Breuer, Peter, Antebi, Adam, Denzel, Martin S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.03.2020; Elsevier
• Subjects: Biological Sciences; Cell Biology; Functional Aspects of Cell Biology; Biological Sciences; Functional Aspects of Cell Biology; Cell Biology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2020.100887

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 eIF2α 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. [Display omitted] •Hexosamine pathway (HP) activation induces the integrated stress response (ISR)•HP activation ameliorates poly-glutamine aggregation via the ISR and autophagy•In C. elegans, the HP/ISR axis improves cell autonomous protein homeostasis•The proteoprotective role of longevity-associated HP is evolutionarily conserved Biological Sciences; Cell Biology; Functional Aspects of Cell Biology