title: NAD(P)H quinone oxidoreductase 1 inhibits the proteasomal degradation of homocysteine-induced endoplasmic reticulum protein.
abstract: Homocysteine-induced endoplasmic reticulum (ER) protein (Herp) is an ER stress-inducible key regulatory component of ER-associated degradation (ERAD) that has been implicated in insulin hypersecretion in diabetic mouse models. Herp expression is tightly regulated. Additionally, Herp is a highly labile protein and interacts with various proteins, which are characteristic features of ubiquitinated protein. Previously, we reported that ubiquitination is not required for Herp degradation. In addition, we found that the lysine residues of Herp (which are ubiquitinated by E3 ubiquitin ligase) are not sufficient for regulation of Herp degradation. In this study, we found that NAD(P)H quinone oxidoreductase 1 (NQO1)-mediated targeting of Herp to the proteasome was involved in Herp degradation. In addition, we found that Herp protein levels were markedly elevated in synoviolin-null cells. The E3 ubiquitin ligase synoviolin is a central component of ERAD and is involved in the degradation of nuclear factor E2-related factor-2 (Nrf2), which regulates cellular reactive oxygen species. Additionally, NQO1 is a target of Nrf2. Thus, our findings indicated that NQO1 could stabilize Herp protein expression via indirect regulation of synoviolin.
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwagun, Iwate, 028-3603, Japan. Electronic address: t-maeda@nichiyaku.ac.jp.
authors.forename: Tomoji
authors.initials: T
authors.lastname: Maeda
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwagun, Iwate, 028-3603, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Tanabe-Fujimura
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwagun, Iwate, 028-3603, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwagun, Iwate, 028-3603, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Abe
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwagun, Iwate, 028-3603, Japan.
authors.forename: Yoshino
authors.initials: Y
authors.lastname: Nanakida
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwagun, Iwate, 028-3603, Japan.
authors.forename: Kun
authors.initials: K
authors.lastname: Zou
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwagun, Iwate, 028-3603, Japan.
authors.forename: Junjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwagun, Iwate, 028-3603, Japan.
authors.forename: Shuyu
authors.initials: S
authors.lastname: Liu
authors.affiliation: Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjyuku, Shinjyuku, Tokyo, Tokyo, 160-8402, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nakajima
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba-Cho, Shiwagun, Iwate, 028-3603, Japan. Electronic address: hkomano@iwate-med.ac.jp.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Komano
mesh_terms: D001665:Binding Sites; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: C485932:HERPUD1 protein, human; D008565:Membrane Proteins; D016660:NAD(P)H Dehydrogenase (Quinone); D046988:Proteasome Endopeptidase Complex
keywords: Degradation; Homocysteine-induced endoplasmic reticulum protein; NAD(P)H quinone oxidoreductase 1; Proteasome