title: Dual regulation of the transcriptional activity of Nrf1 by β-TrCP- and Hrd1-dependent degradation mechanisms.
abstract: A growing body of evidence suggests that Nrf1 is an inducible transcription factor that maintains cellular homeostasis. Under physiological conditions, Nrf1 is targeted to the endoplasmic reticulum (ER), implying that it translocates into the nucleus in response to an activating signal. However, the molecular mechanisms by which the function of Nrf1 is modulated remain poorly understood. Here, we report that two distinct degradation mechanisms regulate Nrf1 activity and the expression of its target genes. In the nucleus, β-TrCP, an adaptor for the SCF (Skp1-Cul1-F-box protein) ubiquitin ligase, promotes the degradation of Nrf1 by catalyzing its polyubiquitination. This activity requires a DSGLS motif on Nrf1, which is similar to the canonical β-TrCP recognition motif. The short interfering RNA (siRNA)-mediated silencing of β-TrCP markedly augments the expression of Nrf1 target genes, such as the proteasome subunit PSMC4, indicating that β-TrCP represses Nrf1 activation. Meanwhile, in the cytoplasm, Nrf1 is degraded and suppressed by the ER-associated degradation (ERAD) ubiquitin ligase Hrd1 and valosin-containing protein (VCP) under normal conditions. We identified a cytoplasmic degradation motif on Nrf1 between the NHB1 and NHB2 domains that exhibited species conservation. Thus, these results clearly suggest that both β-TrCP- and Hrd1-dependent degradation mechanisms regulate the transcriptional activity of Nrf1 to maintain cellular homeostasis.
authors.affiliation: Laboratory for Genetic Cord, Graduate School of Life and Medical Sciences, Doshisha University, 1-3 Tatara Miyakodani, Kyotanabe 610-0394, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Tsuchiya
authors.forename: Tomoko
authors.initials: T
authors.lastname: Morita
authors.forename: Mehee
authors.initials: M
authors.lastname: Kim
authors.forename: Shun-ichiro
authors.initials: S
authors.lastname: Iemura
authors.forename: Tohru
authors.initials: T
authors.lastname: Natsume
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Akira
authors.initials: A
authors.lastname: Kobayashi
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000378:metabolism; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D051379:Mice; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000096:biosynthesis / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D000074405:Valosin Containing Protein; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C471644:BTRC protein, human; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; C495633:NRF1 protein, human; D051266:Nuclear Respiratory Factor 1; D034741:RNA, Small Interfering; D044844:beta-Transducin Repeat-Containing Proteins; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases; C088863:PSMC4 protein, human; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse