title: USP15 negatively regulates Nrf2 through deubiquitination of Keap1.
abstract: Nrf2 is a master regulator of the antioxidant response. Under basal conditions, Nrf2 is polyubiquitinated by the Keap1-Cul3 E3 ligase and degraded by the 26S proteasome. In response to Nrf2 inducers there is a switch in polyubiquitination from Nrf2 to Keap1. Currently, regulation of the Nrf2-Keap1 pathway by ubiquitination is largely understood. However, the mechanism responsible for removal of ubiquitin conjugated to Nrf2 or Keap1 remains unknown. Here we report that the deubiquitinating enzyme, USP15, specifically deubiquitinates Keap1, which suppresses the Nrf2 pathway. We demonstrated that deubiquitinated Keap1 incorporates into the Keap1-Cul3-E3 ligase complex more efficiently, enhancing the complex stability and enzymatic activity. Consequently, there is an increase in Nrf2 protein degradation and a reduction in Nrf2 target gene expression. Furthermore, USP15-siRNA enhances chemoresistance of cells through upregulation of Nrf2. These findings further our understanding of how the Nrf2-Keap1 pathway is regulated, which is imperative in targeting this pathway for chemoprevention or chemotherapy.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Nicole F
authors.initials: NF
authors.lastname: Villeneuve
authors.forename: Wang
authors.initials: W
authors.lastname: Tian
authors.forename: Tongde
authors.initials: T
authors.lastname: Wu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Sun
authors.forename: Alexandria
authors.initials: A
authors.lastname: Lau
authors.forename: Eli
authors.initials: E
authors.lastname: Chapman
authors.forename: Deyu
authors.initials: D
authors.lastname: Fang
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D010450:Endopeptidases / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination
chemical_list: D000975:Antioxidants; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010450:Endopeptidases; C579226:USP15 protein, human; D064570:Ubiquitin-Specific Proteases; D017239:Paclitaxel