title: The COP9 signalosome controls ubiquitinylation of ABCA1.
abstract: ATP-binding cassette protein A1 (ABCA1) mediates the transfer of cellular free cholesterol and phospholipids to apolipoprotein A-I (apoA-I), an extracellular acceptor in plasma, to form high-density lipoprotein (HDL). ABCA1 has been suggested to be degraded by proteasome in cholesterol-loaded macrophages, however, the mechanism and regulation of proteasomal degradation of ABCA1 remain unclear. In this study, we analyzed the putative interaction between ABCA1 and COP9 signalosome (CSN), a key molecule in controlling protein ubiquitination and deubiquitination. CSN2 and CSN5, subunits of COP9 CSN complex, were coprecipitated with ABCA1 when coexpressed in HEK293 cells and proteasomal degradation was inhibited by MG132. Overexpression of CSN2 increased endogenous CSN7 and CSN8, and decreased ubiquitinylated forms of ABCA1. These results suggest that CSN is a key molecule which controls the ubiquitinylation and deubiquitinylation of ABCA1, and is thus an important target for developing potential drugs to prevent atherosclerosis.
authors.affiliation: Laboratory of Cellular Biochemistry, Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Azuma
authors.forename: Mie
authors.initials: M
authors.lastname: Takada
authors.forename: Minami
authors.initials: M
authors.lastname: Maeda
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kioka
authors.forename: Kazumitsu
authors.initials: K
authors.lastname: Ueda
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D050197:Atherosclerosis / Q000378:metabolism*; D000075686:COP9 Signalosome Complex; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D017737:Macrophages, Peritoneal / Q000201:enzymology; D046912:Multiprotein Complexes / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D046912:Multiprotein Complexes; D002784:Cholesterol; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex; D046988:Proteasome Endopeptidase Complex