PUBLICATION
The aspartyl protease DDI2 activates Nrf1 to compensate for proteasome dysfunction
- Authors
- Koizumi, S., Irie, T., Hirayama, S., Sakurai, Y., Yashiroda, H., Naguro, I., Ichijo, H., Hamazaki, J., Murata, S.
- ID
- ZDB-PUB-200522-26
- Date
- 2016
- Source
- eLIFE 5: (Journal)
- Registered Authors
- Keywords
- Nrf1, biochemistry, human, protease, proteasome, transcription
- MeSH Terms
-
- Gene Deletion
- Proteasome Endopeptidase Complex/metabolism*
- Aspartic Acid Proteases/genetics
- Aspartic Acid Proteases/metabolism*
- Nuclear Respiratory Factor 1/metabolism*
- Cell Line
- Genetic Complementation Test
- Humans
- PubMed
- 27528193 Full text @ Elife
Citation
Koizumi, S., Irie, T., Hirayama, S., Sakurai, Y., Yashiroda, H., Naguro, I., Ichijo, H., Hamazaki, J., Murata, S. (2016) The aspartyl protease DDI2 activates Nrf1 to compensate for proteasome dysfunction. eLIFE. 5:.
Abstract
In response to proteasome dysfunction, mammalian cells upregulate proteasome gene expression by activating Nrf1. Nrf1 is an endoplasmic reticulum-resident transcription factor that is continually retrotranslocated and degraded by the proteasome. Upon proteasome inhibition, Nrf1 escapes degradation and is cleaved to become active. However, the processing enzyme for Nrf1 remains obscure. Here we show that the aspartyl protease DNA-damage inducible 1 homolog 2 (DDI2) is required to cleave and activate Nrf1. Deletion of DDI2 reduced the cleaved form of Nrf1 and increased the full-length cytosolic form of Nrf1, resulting in poor upregulation of proteasomes in response to proteasome inhibition. These defects were restored by adding back wild-type DDI2 but not protease-defective DDI2. Our results provide a clue for blocking compensatory proteasome synthesis to improve cancer therapies targeting proteasomes.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping