title: Posttranslational negative regulation of glycosylated and non-glycosylated BCRP expression by Derlin-1.
abstract: Human breast cancer resistance protein (BCRP)/MXR/ABCG2 is a well-recognized ABC half-transporter that is highly expressed at the apical membrane of many normal tissues and cancer cells. BCRP facilitates disposition of endogenous and exogenous harmful xenobiotics to protect cells/tissues from xenobiotic-induced toxicity. Despite the enormous impact of BCRP in the physiological and pathophysiological regulation of the transport of a wide variety of substrates, little is known about the factors that regulate posttranslational expression of BCRP. Here, we identified Derlin-1, a member of a family of proteins that bears homology to yeast Der1p, as a posttranslational regulator of BCRP expression. Overexpression of Derlin-1 suppressed ER to Golgi transport of wild-type (WT) BCRP that is known to be efficiently trafficked to the plasma membrane. On the other hand, protein expression of N596Q variant of BCRP, N-linked glycosylation-deficient mutant that preferentially undergoes ubiquitin-mediated ER-associated degradation (ERAD), was strongly suppressed by the overexpression of Derlin-1, whereas knockdown of Derlin-1 stabilized N596Q protein, suggesting a negative regulatory role of Derlin-1 for N596Q protein expression. Notably, knockdown of Derlin-1 also stabilized the expression of tunicamycin-induced deglycosylated WT BCRP protein, implying the importance of glycosylation state for the recognition of BCRP by Derlin-1. Thus, our data demonstrate that Derlin-1 is a negative regulator for both glycosylated and non-glycosylated BCRP expression and provide a novel posttranslational regulatory mechanism of BCRP by Derlin-1.
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE Cell Fate Regulation Research and Education Unit, Kumamoto University, 5-1 Oe-Honmachi, Kumamoto 862-0973, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sugiyama
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shuto
authors.forename: Shingo
authors.initials: S
authors.lastname: Suzuki
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Koga
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Suico
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Cyr
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kai
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C487709:DERL1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins