Hexosamine Pathway Activation Improves Protein Homeostasis through the Integrated Stress Response

• Main Authors: Moritz Horn, Sarah I. Denzel, Balaji Srinivasan, Kira Allmeroth, Isabelle Schiffer, Vignesh Karthikaisamy, Stephan Miethe, Peter Breuer, Adam Antebi, Martin S. Denzel
• Format: Article
• Language: English
• Published: Elsevier 2020-03-01
• Series: iScience
• Online Access: http://www.sciencedirect.com/science/article/pii/S2589004220300717

Summary: 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. : Biological Sciences; Cell Biology; Functional Aspects of Cell Biology Subject Areas: Biological Sciences, Cell Biology, Functional Aspects of Cell Biology