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.
Highlights
Maintenance of protein homeostasis is essential to all living organisms
An increasing body of evidence suggests that the same signaling pathways that are involved in controlling aging, including insulin/IGF-1 signaling (IIS), regulate the mediators of proteostasis, such as metabolic enzymes, stress proteins, and chaperones (Balch et al, 2008)
We investigate whether IIS contributes to regulation of the ubiquitin-proteasome system (UPS) by using the well-established aging model C. elegans
Summary
Maintenance of protein homeostasis is essential to all living organisms. As an important part of the proteostasis network, the ubiquitin-proteasome system (UPS) executes most of the controlled protein degradation in the cell. There are multiple proteasome-associated proteins possessing essential activities, such as ubiquitin ligases and deubiquitinating enzymes (DUBs), which regulate proteasome function (Finley, 2009; Hanna and Finley, 2007). The proteasome is not a static proteolytic machine; on the contrary, its function is highly regulated (Finley, 2009; Hanna and Finley, 2007). It remains an open question how proteasome activity is regulated in a multicellular organism
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