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      Insulin/IGF-1 signaling regulates proteasome activity through the deubiquitinating enzyme UBH-4.

      Cell Reports
      Animals, Caenorhabditis elegans, Cell Line, Tumor, Humans, Insulin, genetics, metabolism, Insulin-Like Growth Factor I, Proteasome Endopeptidase Complex, Signal Transduction, Transcription Factors

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          Abstract

          The proteasome plays an important role in proteostasis by carrying out controlled protein degradation in the cell. Impairments in proteasome function are associated with severe and often age-related diseases. Here, we have characterized a molecular mechanism linking insulin/IGF-1 signaling (IIS) to proteasome activity. We show that decreased IIS, which promotes proteostasis and longevity, increases proteasome activity through the FOXO transcription factor DAF-16 in C. elegans. Furthermore, we reveal that DAF-16 represses expression of the proteasome-associated deubiquitinating enzyme ubh-4, which we suggest functions as a tissue-specific proteasome inhibitor. Finally, we demonstrate that proteasome activation through downregulation of the ubh-4 human ortholog uchl5 increases degradation of proteotoxic proteins in mammalian cells. In conclusion, we have established a mechanism by which the evolutionarily conserved IIS contributes to the regulation of proteasome activity in a multicellular organism. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

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