title: The aspartyl protease DDI2 activates Nrf1 to compensate for proteasome dysfunction.
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.
authors.affiliation: Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Koizumi
authors.affiliation: Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Irie
authors.affiliation: Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Shoshiro
authors.initials: S
authors.lastname: Hirayama
authors.affiliation: Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sakurai
authors.affiliation: Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Yashiroda
authors.affiliation: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Naguro
authors.affiliation: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.affiliation: Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Hamazaki
authors.affiliation: Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Shigeo
authors.identifier: 0000-0002-3177-3503
authors.initials: S
authors.lastname: Murata
mesh_terms: D057055:Aspartic Acid Proteases / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D017353:Gene Deletion; D005816:Genetic Complementation Test; D006801:Humans; D051266:Nuclear Respiratory Factor 1 / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*
chemical_list: C495633:NRF1 protein, human; D051266:Nuclear Respiratory Factor 1; D057055:Aspartic Acid Proteases; C000624278:DDI2 protein, human; D046988:Proteasome Endopeptidase Complex
keywords: Nrf1; biochemistry; human; protease; proteasome; transcription