title: USP15 stabilizes the transcription factor Nrf1 in the nucleus, promoting the proteasome gene expression.
abstract: The transcriptional factor Nrf1 (NF-E2-related factor 1) sustains protein homeostasis (proteostasis) by regulating the expression of proteasome genes. Under physiological conditions, the transcriptional activity of Nrf1 is repressed by its sequestration into the endoplasmic reticulum (ER) and furthermore by two independent ubiquitin-proteasome pathways, comprising Hrd1 and β-TrCP in the cytoplasm and nucleus, respectively. However, the molecular mechanisms underlying Nrf1 activation remain unclear. Here, we report that USP15 (Ubiquitin-Specific Protease 15) activates Nrf1 in the nucleus by stabilizing it through deubiquitination. We first identified USP15 as an Nrf1-associated factor through proteome analysis. USP15 physically interacts with Nrf1, and it markedly stabilizes Nrf1 by removing its ubiquitin moieties. USP15 activates the Nrf1-mediated expression of a proteasome gene luciferase reporter and endogenous proteasome activity. The siRNA-mediated knockdown of USP15 diminishes the Nrf1-induced proteasome gene expression in response to proteasome inhibition. These results uncover a new regulatory mechanism that USP15 activates Nrf1 against the β-TrCP inhibition to maintain proteostasis.
authors.affiliation: Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Fukagai
authors.affiliation: Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Waku
authors.affiliation: Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan.
authors.forename: A M Masudul Azad
authors.initials: AMMA
authors.lastname: Chowdhury
authors.affiliation: Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Kubo
authors.affiliation: Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kato
authors.affiliation: National Institutes of Advanced Industrial Science and Technology, Biological Information Research Center (JBIRC), Tokyo, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Natsume
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Fuminori
authors.initials: F
authors.lastname: Tsuruta
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Chiba
authors.affiliation: Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Taniguchi
authors.affiliation: Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto, Japan. Electronic address: akobayas@mail.doshisha.ac.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Kobayashi
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051266:Nuclear Respiratory Factor 1 / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: C495633:NRF1 protein, human; D051266:Nuclear Respiratory Factor 1; D014157:Transcription Factors; C579226:USP15 protein, human; D064570:Ubiquitin-Specific Proteases; D046988:Proteasome Endopeptidase Complex
keywords: Deubiquitination; Gene regulation; Proteasomal degradation; Transcription factor; Ubiquitination