Universität zu Köln

Horn, Moritz, Denzel, Sarah, I, Srinivasan, Balaji, Allmeroth, Kira, Schiffer, Isabelle, Karthikaisamy, Vignesh, Miethe, Stephan, Breuer, Peter, Antebi, Adam and Denzel, Martin S. (2020). Hexosamine Pathway Activation Improves Protein Homeostasis through the Integrated Stress Response. iScience, 23 (3). CAMBRIDGE: CELL PRESS. ISSN 2589-0042

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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 eIF2 alpha 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Horn, Moritz UNSPECIFIED UNSPECIFIED UNSPECIFIED Denzel, Sarah, I UNSPECIFIED UNSPECIFIED UNSPECIFIED Srinivasan, Balaji UNSPECIFIED UNSPECIFIED UNSPECIFIED Allmeroth, Kira UNSPECIFIED UNSPECIFIED UNSPECIFIED Schiffer, Isabelle UNSPECIFIED UNSPECIFIED UNSPECIFIED Karthikaisamy, Vignesh UNSPECIFIED UNSPECIFIED UNSPECIFIED Miethe, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED Breuer, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Antebi, Adam UNSPECIFIED UNSPECIFIED UNSPECIFIED Denzel, Martin S. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-340147
DOI:	10.1016/j.isci.2020.100887
Journal or Publication Title:	iScience
Volume:	23
Number:	3
Date:	2020
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	2589-0042
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TRANSLATIONAL CONTROL; SUPEROXIDE-DISMUTASE; GENE; AUTOPHAGY; AGGREGATION; DISEASE; ATF4; PHOSPHORYLATION; HUNTINGTIN; QUANTIFICATION Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/34014