Protein kinase A modulates the activity of a major human isoform of ABCG1

Journal of Lipid Research

Leonard Kritharides¹  Laura J. Sharpe²  Geetha Rao³  Andrew J. Brown⁴  Maaike Kockx⁴  Cecilia Sandoval⁵  Wendy Jessup⁵  Ingrid C. Gelissen⁶ 

[1] Department of Haematology, Prince of Wales Hospital, Sydney, Australia;Faculty of Pharmacy, University of Sydney, Sydney, Australia;School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia;Centre for Vascular Research, University of New South Wales, Sydney, Australia;Faculty of Pharmacy, University of Sydney, Sydney, Australia;To whom correspondence should be addressed;

关键词: ATP binding cassette transporters;    cholesterol efflux;    high-density lipoprotein;    protein stability;    phosphorylation;   

DOI  :  

来源: DOAJ

【 摘 要 】

ABCG1 is an ABC half-transporter that exports cholesterol from cells to HDL. This study set out to investigate differences in posttranslational processing of two human ABCG1 protein isoforms, termed ABCG1(+12) and ABCG1(− 12), that differ by the presence or absence of a 12 amino acid peptide. ABCG1(+12) is expressed in human cells and tissues, but not in mice. We identified two protein kinase A (PKA) consensus sites in ABCG1(+12), absent from ABCG1(− 12). Inhibition of PKA with either of two structurally unrelated inhibitors resulted in a dose-dependent increase in cholesterol export from cells expressing ABCG1(+12), whereas ABCG1(− 12)-expressing cells were unaffected. This was associated with stabilization of the ABCG1(+12) protein, and ABCG1(+12)-S389 was necessary to mediate these effects. Mutation of this serine to aspartic acid, simulating a constitutively phosphorylated state, resulted in accelerated degradation of ABCG1(+12) and reduced cholesterol export. Engineering an equivalent PKA site into ABCG1(− 12) rendered this isoform responsive to PKA inhibition, confirming the relevance of this sequence. Together, these results demonstrate an additional level of complexity to the posttranslational control of this human ABCG1 isoform that is absent from ABCG1(− 12) and the murine ABCG1 homolog.

【 授权许可】

Unknown