title: Insulin/IGF-1 signaling regulates proteasome activity through the deubiquitinating enzyme UBH-4.
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.
authors.affiliation: Research Programs Unit, Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, FI-00290 Helsinki, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Matilainen
authors.forename: Leena
authors.initials: L
authors.lastname: Arpalahti
authors.forename: Ville
authors.initials: V
authors.lastname: Rantanen
authors.forename: Sampsa
authors.initials: S
authors.lastname: Hautaniemi
authors.forename: Carina I
authors.initials: CI
authors.lastname: Holmberg
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans; D045744:Cell Line, Tumor; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D007328:Insulin; D014157:Transcription Factors; D007334:Insulin-Like Growth Factor I; D046988:Proteasome Endopeptidase Complex