RRC ID 53316
著者 Lehrbach NJ, Ruvkun G.
タイトル Proteasome dysfunction triggers activation of SKN-1A/Nrf1 by the aspartic protease DDI-1.
ジャーナル Elife
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.
巻・号 5
公開日 2016-8-16
DOI 10.7554/eLife.17721
PII e17721
PMID 27528192
PMC PMC4987142
MeSH Animals Aspartic Acid Proteases / metabolism* Caenorhabditis elegans / enzymology* Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / metabolism* DNA-Binding Proteins / metabolism* Gene Expression Regulation* Proteasome Endopeptidase Complex / metabolism* Transcription Factors / metabolism*
IF 7.08
引用数 73
リソース情報
線虫 tm1743