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Resources » Paper

Tremmel, Sarah I. et al. (2015) International Worm Meeting "How does the Hexosamine Pathway regulate Protein Quality Control and Longevity?"

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  • Comments on Tremmel, Sarah I. et al. (2015) International Worm Meeting "How does the Hexosamine Pathway regulate Protein Quality Control and Longevity?" (0)

  • Overview

    Status:
    Publication type:
    Meeting_abstract
    WormBase ID:
    WBPaper00047659

    Tremmel, Sarah I., & Antebi, Adam (2015). How does the Hexosamine Pathway regulate Protein Quality Control and Longevity? presented in International Worm Meeting. Unpublished information; cite only with author permission.

    The metabolic hexosamine pathway (HP) uses the glycolysis intermediate fructose 6-phosphate to produce UDP-N-acetylglucosamine (UDP-GlcNAc). This aminosugar is an essential building block for protein N-glycosylation, which assists protein folding and secretion and protein O-glycosylation with diverse functions in protein homeostasis, protein stability and regulation of protein function. In Caenorhabditis elegans, UDP-GlcNAc levels can be increased by overexpression (OE) or gain-of-function (gof) mutations in the HP's rate-limiting enzyme glutamine fructose-6-phosphate aminotransferase (gfat-1) as well as by supplementation of UDP-GlcNAc precursor N-acetylglucosamine (GlcNAc) in the food. This results in resistance to tunicamycin, a drug that inhibits protein N-glycosylation, improved protein quality control (PQC) and extended lifespan.We are aiming to understand (I) how these beneficial changes are evoked by an increase in the endogenous metabolite UDP-GlcNAc. Global approaches like SILAC labeling of worms and consecutive MS analysis will reveal gfat-1 gof induced changes in the proteome, and a genetic yeast screen will be deployed to identify mediators of HP activation.(II) We are testing the hypothesis that gfat-1 activation might be part of the endogenous stress response. For that purpose, expression levels and expression pattern of GFAT-1 after exposure to diverse stressors are analyzed and stress resistance of gfat-1 gof mutants will be assessed.(III) The HP pathway is essential for an organism's survival, yet some indications point to an additional tissue-specific function in regulation of PQC and lifespan. To challenge this idea we are generating tissue-specific gfat-1 overexpressing lines and examine them with regard to PQC mechanisms and longevity. Here, preliminary data suggest that neuronal overexpression of gfat-1 is sufficient to increase tunicamycin resistance compared to wildtype controls.Together, this project aims to understand how the HP links aminosugar production with enhanced PQC and extended health- and lifespan.

    Affiliation:
    - Max-Planck-Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, 50931 Cologne, Germany


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