Insulin/IGF-1 Signaling Regulates Proteasome Activity through the Deubiquitinating Enzyme UBH-4

• Published in: Cell reports (Cambridge) 2013-06, Vol.3 (6), p.1980-1995
• Main Authors: Matilainen, Olli, Arpalahti, Leena, Rantanen, Ville, Hautaniemi, Sampsa, Holmberg, Carina I.
• Format: Article
• Language: English
• Subjects: Animals; Caenorhabditis elegans; Cell Line, Tumor; Humans; Insulin - genetics; Insulin - metabolism; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Signal Transduction; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.05.012

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. [Display omitted] •Insulin/IGF-1 signaling regulates proteasome activity in C. elegans•DAF-16 represses expression of the deubiquitinating enzyme ubh-4•ubh-4 downregulation increases proteasome activity•Knockdown of mammalian ortholog uchl5 increases degradation of proteotoxic proteins The proteasome plays an essential role in the maintenance of cellular protein homeostasis. Here, Holmberg and colleagues report a molecular mechanism by which the evolutionarily conserved insulin/IGF-1 signaling pathway regulates proteasome activity through the transcription factor DAF-16 in C. elegans. DAF-16 inhibits the expression of deubiquitinating enzyme ubh-4, which functions as a tissue-specific proteasome inhibitor. Deciphering cell-type specificity provides a better understanding of proteasome regulation and may aid the development of new targets for therapeutic interventions in proteasome-related diseases.