title: Genome-wide identification and gene expression profiling of ubiquitin ligases for endoplasmic reticulum protein degradation.
abstract: Endoplasmic reticulum (ER)-associated degradation (ERAD) is a mechanism by which unfolded proteins that accumulate in the ER are transported to the cytosol for ubiquitin-proteasome-mediated degradation. Ubiquitin ligases (E3s) are a group of enzymes responsible for substrate selectivity and ubiquitin chain formation. The purpose of this study was to identify novel E3s involved in ERAD. Thirty-seven candidate genes were selected by searches for proteins with RING-finger motifs and transmembrane regions, which are the major features of ERAD E3s. We performed gene expression profiling for the identified E3s in human and mouse tissues. Several genes were specifically or selectively expressed in both tissues; the expression of four genes (RNFT1, RNF185, CGRRF1 and RNF19B) was significantly upregulated by ER stress. To determine the involvement of the ER stress-responsive genes in ERAD, we investigated their ER localisation, in vitro autoubiquitination activity and ER stress resistance. All were partially localised to the ER, whereas CGRRF1 did not possess E3 activity. RNFT1 and RNF185, but not CGRRF1 and RNF19B, exhibited significant resistance to ER stressor in an E3 activity-dependent manner. Thus, these genes are possible candidates for ERAD E3s.
authors.affiliation: Department of Biochemistry, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kaneko
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Iwase
authors.affiliation: Otsuka GEN Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima 771-0192, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yamasaki
authors.affiliation: Department of Biochemistry, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takai
authors.affiliation: Department of Biochemistry, Graduate school of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
authors.forename: Soshi
authors.initials: S
authors.lastname: Kanemoto
authors.affiliation: Department of Biochemistry, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Matsuhisa
authors.affiliation: Department of Biochemistry, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Asada
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Chiba Institute of Science, Choshi, Chiba 288-0025, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Okuma
authors.affiliation: Otsuka GEN Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima 771-0192, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Biochemistry, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Imaizumi
authors.affiliation: Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan.
authors.forename: Yausyuki
authors.initials: Y
authors.lastname: Nomura
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics
chemical_list: D044767:Ubiquitin-Protein Ligases