期刊
EUROPEAN HEART JOURNAL
卷 41, 期 2, 页码 239-+出版社
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehz566
关键词
Proprotein convertase subtilisin/kexin type-9; Low-density lipoprotein receptor; Cyclase-associated protein 1; LDL cholesterol; Endocytosis; Caveolae
资金
- National Research Foundation of Korea (NRF) - Korea Government (MSIP) [NRF-2017R1D1A1A02017804]
- Korea Health Technology R&D Project 'Korea Research-Driven Hospital' through the Korea Health Industry Development Institute (KHIDI) - Korea Government (MHW) [HI14C1277]
- Korea Health Technology R&D Project 'Strategic Center of Cell & Bio Therapy' through the Korea Health Industry Development Institute (KHIDI) - Korea Government (MHW) [HI17C2085]
- Korea Health Technology R&D Project ''Medi-star ' through the Korea Health Industry Development Institute (KHIDI) - Korea Government (MHW) [HI12C1691]
Aims Proprotein convertase subtilisin/kexin type-9 (PCSK9), a molecular determinant of low-density lipoprotein (LDL) receptor (LDLR) fate, has emerged as a promising therapeutic target for atherosclerotic cardiovascular diseases. However, the precise mechanism by which PCSK9 regulates the internalization and lysosomal degradation of LDLR is unknown. Recently, we identified adenylyl cyclase-associated protein 1 (CAP1) as a receptor for human resistin whose globular C-terminus is structurally similar to the C-terminal cysteine-rich domain (CRD) of PCSK9. Herein, we investigated the rote of CAP1 in PCSK9-mediated lysosomal degradation of LDLR and plasma LDL cholesterol (LDL-C) levels. Mehods and results The direct binding between PCSK9 and CAP1 was confirmed by immunoprecipitation assay, far-western blot, bio- and results molecular fluorescence complementation, and surface plasmon resonance assay. Fine mapping revealed that the CRD of PCSK9 binds with the Src homology 3 binding domain (SH3BD) of CAP1. Two loss-of-function polymorphisms found in human PCSK9 (S668R and G670E in CRD) were attributed to a defective interaction with CAP1. siRNA against CAP1 reduced the PCSK9-mediated degradation of LDLR in vitro. We generated CAP1 knock-out mice and found that the viable heterozygous CAP1 knock-out mice had higher protein levels of LDLR and lower LDL-C levels in the liver and plasma, respectively, than the control mice. Mechanistic analysis revealed that PCSK9-induced endocytosis and lysosomal degradation of LDLR were mediated by caveolin but not by clathrin, and they were dependent on binding between CAP1 and caveolin-1. Conclusion We identified CAM as a new binding partner of PCSK9 and a key mediator of caveolae-dependent endocytosis and lysosomal degradation of LDLR.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据