Proteasome dysfunction triggers activation of SKN-1A/Nrf1 by the aspartic protease DDI-1

Area of Science:

• Cellular Biology
• Molecular Biology
• Genetics

Background:

• Proteasomes maintain protein homeostasis in eukaryotes.
• Proteasome dysfunction triggers compensatory gene expression.
• SKN-1, a transcription factor, is crucial for this response in C. elegans.

Purpose of the Study:

• To elucidate the pathway for detecting proteasome dysfunction and activating SKN-1 in C. elegans.
• To identify key molecular players involved in proteasome surveillance.

Main Methods:

• Comprehensive genetic analyses in Caenorhabditis elegans.
• Investigated gene expression patterns under proteasome stress.
• Characterized the role of DDI-1 in SKN-1 activation.

Main Results:

• Identified regulators of ER traffic, a peptide N-glycanase, and DDI-1 protease as essential for SKN-1 activation.
• DDI-1 expression is upregulated upon proteasome dysfunction.
• DDI-1 cleaves and activates an ER-associated SKN-1 isoform.

Conclusions:

• A conserved pathway for proteasome surveillance exists, involving DDI-1 protease-mediated activation of SKN-1.
• This mechanism is conserved in mammals, with Nrf1 also being ER-associated and proteolytically processed.
• Targeting DDI1 could offer therapeutic strategies for aging, protein aggregation disorders, and cancer chemotherapy.