Horn Moritz, Denzel Sarah I, Srinivasan Balaji, Allmeroth Kira, Schiffer Isabelle, Karthikaisamy Vignesh, Miethe Stephan, Breuer Peter, Antebi Adam, Denzel Martin S
Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, 50931 Cologne, Germany.
University of Bonn, Department of Neurology, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
iScience. 2020 Mar 27;23(3):100887. doi: 10.1016/j.isci.2020.100887. Epub 2020 Feb 5.
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.
通过其限速酶谷氨酰胺果糖-6-磷酸酰胺转移酶（GFAT-1）的功能获得性突变激活己糖胺途径（HP），可改善蛋白质毒性并延长秀丽隐杆线虫的寿命。在此，我们研究HP在哺乳动物蛋白质质量控制中的作用。在小鼠神经元细胞中，HP活性升高导致PERK和eIF2α磷酸化以及下游ATF4激活，表明HP是综合应激反应（ISR）的调节因子。通过GFAT1功能获得性突变或补充前体GlcNAc增加尿苷5'-二磷酸-N-乙酰-D-葡萄糖胺（UDP-GlcNAc）水平，可减少多聚谷氨酰胺（polyQ）蛋白Ataxin-3的聚集。阻断PERK信号传导或自噬可抑制这种作用。在秀丽隐杆线虫中，gfat-1的过表达同样会激活ISR。一致地，在肌肉中共同过表达gfat-1和具有蛋白质毒性的polyQ肽揭示了HP强大的细胞自主保护作用。因此，HP通过调节ISR在改善蛋白质质量控制方面具有保守作用。
