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

Nicolas J Lehrbach,Gary Ruvkun

doi:10.7554/elife.17721

Abstract

Proteasomes are essential for protein homeostasis in eukaryotes. To preserve cellular function, transcription of proteasome subunit genes is induced in response to proteasome dysfunction caused by pathogen attacks or proteasome inhibitor drugs. In Caenorhabditis elegans, this response requires SKN-1, a transcription factor related to mammalian Nrf1/2. Here, we use comprehensive genetic analyses to identify the pathway required for C. elegans to detect proteasome dysfunction and activate SKN-1. Genes required for SKN-1 activation encode regulators of ER traffic, a peptide N-glycanase, and DDI-1, a conserved aspartic protease. DDI-1 expression is induced by proteasome dysfunction, and we show that DDI-1 is required to cleave and activate an ER-associated isoform of SKN-1. Mammalian Nrf1 is also ER-associated and subject to proteolytic cleavage, suggesting a conserved mechanism of proteasome surveillance. Targeting mammalian DDI1 protease could mitigate effects of proteasome dysfunction in aging and protein aggregation disorders, or increase effectiveness of proteasome inhibitor cancer chemotherapies.

Highlights

The proteasome is a multi-protein complex responsible for the majority of protein degradation in eukaryotic cells (Tomko and Hochstrasser, 2013)
The aspartic protease DDI-1 and ER-associated degradation (ERAD) factors are required for transcriptional responses to proteasome disruption
The proteasome subunit gene rpt-3 is upregulated in a skn-1-dependent manner in response to proteasome disruption (Li et al, 2011)

Summary

Introduction

The proteasome is a multi-protein complex responsible for the majority of protein degradation in eukaryotic cells (Tomko and Hochstrasser, 2013). Production of small molecule inhibitors and protein virulence factors that target the proteasome by some bacteria and fungi exploits this vulnerability to gain a growth advantage (Fenteany et al, 1995; Groll et al, 2008; Meng et al, 1999). A conserved response to proteasome disruption is the transcriptional up-regulation of proteasome subunit genes (Fleming, 2002; Meiners et al, 2003; Wojcik and DeMartino, 2002). Two CnC-bZip franscription factors, Nrf1/NFE2L1 and Nrf, have similar DNA-binding domains and may regulate an overlapping set of downstream targets.

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