OBJECTIVE: Cell-surface localization and intracellular trafficking are essential for the function of ATP-binding cassette transporter A-1 (ABCA1). However, regulation of these activities is still largely unknown. Brefeldin A, an uncompetitive inhibitor of brefeldin A-inhibited guanine nucleotide-exchange proteins (BIGs), disturbs the intracellular distribution of ABCA1, and thus inhibits cholesterol efflux. This study aimed to define the possible roles of BIGs in regulating ABCA1 trafficking and cholesterol efflux, and further to explore the potential mechanism. METHODS AND RESULTS: By vesicle immunoprecipitation, we found that BIG1 was associated with ABCA1 in vesicles preparation from rat liver. BIG1 depletion reduced surface ABCA1 on HepG2 cells, and inhibited by 60% cholesterol release. In contrast, BIG1 overexpression increased surface ABCA1 and cholesterol secretion. With partial restoration of BIG1 through overexpression in BIG1-depleted cells, surface ABCA1 was also restored. Biotinylation and glutathione cleavage revealed that BIG1 small interfering RNA dramatically decreased the internalization and recycling of ABCA1. This novel function of BIG1 was dependent on the guanine nucleotide-exchange activity and achieved through activation of ADP-ribosylation factor 1. CONCLUSIONS: BIG1, through its ability to activate ADP-ribosylation factor 1, regulates cell-surface levels and function of ABCA1, indicating a transcription-independent mechanism for controlling ABCA1 action.
OBJECTIVE: Cell-surface localization and intracellular trafficking are essential for the function of ATP-binding cassette transporter A-1 (ABCA1). However, regulation of these activities is still largely unknown. Brefeldin A, an uncompetitive inhibitor of brefeldin A-inhibited guanine nucleotide-exchange proteins (BIGs), disturbs the intracellular distribution of ABCA1, and thus inhibits cholesterol efflux. This study aimed to define the possible roles of BIGs in regulating ABCA1 trafficking and cholesterol efflux, and further to explore the potential mechanism. METHODS AND RESULTS: By vesicle immunoprecipitation, we found that BIG1 was associated with ABCA1 in vesicles preparation from rat liver. BIG1 depletion reduced surface ABCA1 on HepG2 cells, and inhibited by 60% cholesterol release. In contrast, BIG1 overexpression increased surface ABCA1 and cholesterol secretion. With partial restoration of BIG1 through overexpression in BIG1-depleted cells, surface ABCA1 was also restored. Biotinylation and glutathione cleavage revealed that BIG1 small interfering RNA dramatically decreased the internalization and recycling of ABCA1. This novel function of BIG1 was dependent on the guanine nucleotide-exchange activity and achieved through activation of ADP-ribosylation factor 1. CONCLUSIONS:BIG1, through its ability to activate ADP-ribosylation factor 1, regulates cell-surface levels and function of ABCA1, indicating a transcription-independent mechanism for controlling ABCA1 action.
Authors: E B Neufeld; A T Remaley; S J Demosky; J A Stonik; A M Cooney; M Comly; N K Dwyer; M Zhang; J Blanchette-Mackie; S Santamarina-Fojo; H B Brewer Journal: J Biol Chem Date: 2001-05-10 Impact factor: 5.157
Authors: Michael F Beers; Arie Hawkins; Henry Shuman; Ming Zhao; Jennifer L Newitt; Jean Ann Maguire; Wenge Ding; Surafel Mulugeta Journal: J Lipid Res Date: 2011-05-17 Impact factor: 5.922
Authors: R Yamaji; R Adamik; K Takeda; A Togawa; G Pacheco-Rodriguez; V J Ferrans; J Moss; M Vaughan Journal: Proc Natl Acad Sci U S A Date: 2000-03-14 Impact factor: 11.205
Authors: A Chawla; W A Boisvert; C H Lee; B A Laffitte; Y Barak; S B Joseph; D Liao; L Nagy; P A Edwards; L K Curtiss; R M Evans; P Tontonoz Journal: Mol Cell Date: 2001-01 Impact factor: 17.970
Authors: A Venkateswaran; B A Laffitte; S B Joseph; P A Mak; D C Wilpitz; P A Edwards; P Tontonoz Journal: Proc Natl Acad Sci U S A Date: 2000-10-24 Impact factor: 11.205
Authors: Federica Basso; Lita Freeman; Catherine L Knapper; Alan Remaley; John Stonik; Edward B Neufeld; Terese Tansey; Marcelo J A Amar; Jamila Fruchart-Najib; Nicholas Duverger; Silvia Santamarina-Fojo; H Bryan Brewer Journal: J Lipid Res Date: 2002-11-04 Impact factor: 5.922
Authors: Ritwik Datta; Carlos O Lizama; Amin K Soltani; William Mckleroy; Michael J Podolsky; Christopher D Yang; Tony L Huynh; Kelly M Cautivo; Biao Wang; Suneil K Koliwad; Nada A Abumrad; Kamran Atabai Journal: Proc Natl Acad Sci U S A Date: 2021-05-04 Impact factor: 11.205