Phosphorylation by protein kinase C stabilizes ABCG1 and increases cholesterol efflux

被引:11
|
作者
Watanabe, Taro [1 ]
Kioka, Noriyuki [1 ]
Ueda, Kazumitsu [1 ,2 ]
Matsuo, Michinori [1 ,3 ]
机构
[1] Kyoto Univ, Grad Sch Agr, Div Appl Life Sci, Lab Cellular Biochem, Kyoto 6068502, Japan
[2] Kyoto Univ, Inst Integrated Cell Mat Sci WPI iCeMS, Kyoto 6068501, Japan
[3] Kyoto Womens Univ, Fac Home Econ, Dept Food & Nutr, Kyoto 6058501, Japan
来源
JOURNAL OF BIOCHEMISTRY | 2019年 / 166卷 / 04期
关键词
ABC protein; atherosclerosis; cholesterol; high-density lipoprotein (HDL); transporter; CASSETTE TRANSPORTER A1; ABCA1; HDL; DEGRADATION; MACROPHAGES; EXPRESSION; SEQUENCE; G1;
D O I
10.1093/jb/mvz039
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
ATP-binding cassette protein G1 (ABCG1) plays an important role in eliminating excess cholesterol from macrophages and in the formation of high-density lipoprotein (HDL), which contributes to the prevention and regression of atherosclerosis. The post-translational regulation of ABCG1 remains elusive, although phosphorylation by protein kinase A destabilizes ABCG1 proteins. We examined the phosphorylation of ABCG1 using HEK293 and Raw264.7 cells. ABCG1 phosphorylation was enhanced by treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA), a protein kinase C (PKC) activator. PKC activation by TPA increased ABCG1 protein levels and promoted ABCG1-dependent cholesterol efflux to HDL. This activity was suppressed by Go6976, a PKC alpha/beta I inhibitor, suggesting that PKC activation stabilizes ABCG1. To confirm this, the degradation rate of ABCG1 was analysed; ABCG1 degradation was suppressed upon PKC activation, suggesting that PKC phosphorylation regulates ABCG1 levels. To confirm this involvement, we co-expressed ABCG1 and a constitutively active form of PKC alpha in HEK cells. ABCG1 was increased upon co-expression. These results suggest that PKC-mediated phosphorylation, probably PKC alpha, stabilizes ABCG1, consequently increasing ABCG1-mediated cholesterol efflux, by suppressing ABCG1 degradation. PKC activation could thus be a therapeutic target to suppress the development of atherosclerosis.
引用
收藏
页码:309 / 315
页数:7
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