Hexosamine Pathway Activation Improves Protein Homeostasis through the Integrated Stress Response.
Biological Sciences
Cell Biology
Functional Aspects of Cell Biology
Journal
iScience
ISSN: 2589-0042
Titre abrégé: iScience
Pays: United States
ID NLM: 101724038
Informations de publication
Date de publication:
27 Mar 2020
27 Mar 2020
Historique:
received:
23
04
2019
revised:
24
10
2019
accepted:
08
01
2020
pubmed:
23
2
2020
medline:
23
2
2020
entrez:
23
2
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32086012
pii: S2589-0042(20)30071-7
doi: 10.1016/j.isci.2020.100887
pmc: PMC7033349
pii:
doi:
Types de publication
Journal Article
Langues
eng
Pagination
100887Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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