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Aging is attended by a progressive decline in protein homeostasis (proteostasis), aggravating the risk for protein aggregation diseases. To understand the coordination between proteome imbalance and longevity, we addressed the mechanistic role of the quality-control ubiquitin ligase CHIP, which is a key regulator of proteostasis. We observed that CHIP deficiency leads to increased levels of the insulin receptor (INSR) and reduced lifespan of worms and flies. The membrane-bound INSR regulates the insulin and IGF1 signaling (IIS) pathway and thereby defines metabolism and aging. INSR is a direct target of CHIP, which triggers receptor monoubiquitylation and endocytic-lysosomal turnover to promote longevity. However, upon proteotoxic stress conditions and during aging, CHIP is recruited toward disposal of misfolded proteins, reducing its capacity to degrade the INSR. Our study indicates a competitive relationship between proteostasis and longevity regulation through CHIP-assisted proteolysis, providing a mechanistic concept for understanding the impact of proteome imbalance on aging.
Pubmed ID: 28431247 RIS Download
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A commercial antibody supplier and provider of various services.
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View all literature mentionsCaenorhabditis elegans with name daf-16(mgDf50) I; daf-2(e1370) III from WB.
View all literature mentionsThis monoclonal targets Penta-His
View all literature mentionsThis polyclonal targets Stub1
View all literature mentionsThis polyclonal targets TUBG1, TUBG2
View all literature mentionsThis polyclonal targets INSR
View all literature mentionsThis monoclonal targets IGF-I Receptor (D23H3) XP Rabbit mAb
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View all literature mentionsThis polyclonal targets Phospho-Drosophila Akt (Ser505)
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View all literature mentionsThis unknown targets Rabbit IgG (H+L)
View all literature mentionsThis polyclonal targets IgG (H + L)
View all literature mentionsThis monoclonal targets alpha-Tubulin antibody produced in mouse
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View all literature mentionsThis is a legacy resource.
View all literature mentionsCell line HeLa is a Cancer cell line with a species of origin Homo sapiens
View all literature mentionsCell line HEK293 is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsDrosophila melanogaster with name w[1118] from BDSC.
View all literature mentionsDrosophila melanogaster with name y[1] w[*]; P{w[+mC]=Act5C-GAL4}17bFO1/TM6B, Tb[1] from BDSC.
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