title: Cellular cholesterol regulates ubiquitination and degradation of the cholesterol export proteins ABCA1 and ABCG1.
abstract: The objective of this study was to examine the influence of cholesterol in post-translational control of ABCA1 and ABCG1 protein expression. Using CHO cell lines stably expressing human ABCA1 or ABCG1, we observed that the abundance of these proteins is increased by cell cholesterol loading. The response to increased cholesterol is rapid, is independent of transcription, and appears to be specific for these membrane proteins. The effect is mediated through cholesterol-dependent inhibition of transporter protein degradation. Cell cholesterol loading similarly regulates degradation of endogenously expressed ABCA1 and ABCG1 in human THP-1 macrophages. Turnover of ABCA1 and ABCG1 is strongly inhibited by proteasomal inhibitors and is unresponsive to inhibitors of lysosomal proteolysis. Furthermore, cell cholesterol loading inhibits ubiquitination of ABCA1 and ABCG1. Our findings provide evidence for a rapid, cholesterol-dependent, post-translational control of ABCA1 and ABCG1 protein levels, mediated through a specific and sterol-sensitive mechanism for suppression of transporter protein ubiquitination, which in turn decreases proteasomal degradation. This provides a mechanism for acute fine-tuning of cholesterol transporter activity in response to fluctuations in cell cholesterol levels, in addition to the longer term cholesterol-dependent transcriptional regulation of these genes.
authors: From the Atherosclerosis Laboratory, ANZAC Research Institute and.
authors: Victar
authors: V
authors: Hsieh
authors: Mi-Jurng
authors: MJ
authors: Kim
authors: Ingrid C
authors: IC
authors: Gelissen
authors: Andrew J
authors: AJ
authors: Brown
authors: Cecilia
authors: C
authors: Sandoval
authors: Jeannette C
authors: JC
authors: Hallab
authors: Maaike
authors: M
authors: Kockx
authors: Mathew
authors: M
authors: Traini
authors: Wendy
authors: W
authors: Jessup
authors: Leonard
authors: L
authors: Kritharides
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism*; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism; D001692:Biological Transport; D016466:CHO Cells; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D003412:Cricetulus; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D061988:Proteasome Inhibitors; D025801:Ubiquitin; D002784:Cholesterol; D046988:Proteasome Endopeptidase Complex
keywords: ABC Transporter; ABCA1; ABCG1; Cholesterol; Proteasome; Protein Degradation; Ubiquitination