ausblenden:
Schlagwörter:
Amino Acid Sequence
Animals
Autophagy
*Biosynthetic Pathways
Caenorhabditis elegans/enzymology/genetics/*metabolism
Caenorhabditis elegans Proteins/genetics/*metabolism
Endoplasmic Reticulum/metabolism
Endoplasmic Reticulum Stress
Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)/genetics/*metabolism
Hexosamines/*metabolism
Humans
*Longevity
Molecular Sequence Data
Mutation
Protein Biosynthesis
Proteins/*metabolism
Sequence Alignment
Tunicamycin/pharmacology
Zusammenfassung:
Aging entails a progressive decline in protein homeostasis, which often leads to age-related diseases. The endoplasmic reticulum (ER) is the site of protein synthesis and maturation for secreted and membrane proteins. Correct folding of ER proteins requires covalent attachment of N-linked glycan oligosaccharides. Here, we report that increased synthesis of N-glycan precursors in the hexosamine pathway improves ER protein homeostasis and extends lifespan in C. elegans. Addition of the N-glycan precursor N-acetylglucosamine to the growth medium slows aging in wild-type animals and alleviates pathology of distinct neurotoxic disease models. Our data suggest that reduced aggregation of metastable proteins and lifespan extension depend on enhanced ER-associated protein degradation, proteasomal activity, and autophagy. Evidently, hexosamine pathway activation or N-acetylglucosamine supplementation induces distinct protein quality control mechanisms, which may allow therapeutic intervention against age-related and proteotoxic diseases.
