Open AccessCyclase-associated protein 1 is a binding partner of proprotein convertase subtilisin/kexin type-9 and is required for the degradation of low-density lipoprotein receptors by proprotein convertase subtilisin/kexin type-9
Author(s) -
Hyun Duk Jang,
Sang Eun Lee,
Jeyul Yang,
Hyun Chae Lee,
Dasom Shin,
Hwan Lee,
Jaewon Lee,
Shaohua Jin,
Soungchan Kim,
Seung Ji Lee,
Jihye You,
Hyun Woo Park,
Ky Youb Nam,
Sang Hak Lee,
Park Sw,
Jin-Soo Kim,
Sang Yeob Kim,
Yoo Wook Kwon,
Soo Heon Kwak,
Han Mo Yang,
Hyo Soo Kim
Publication year - 2019
Publication title -
european heart journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.336
H-Index - 293
eISSN - 1522-9645
pISSN - 0195-668X
DOI - 10.1093/eurheartj/ehz566
Subject(s) - proprotein convertase , kexin , pcsk9 , ldl receptor , internalization , microbiology and biotechnology , receptor , biology , biochemistry , lipoprotein , cholesterol
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 role of CAP1 in PCSK9-mediated lysosomal degradation of LDLR and plasma LDL cholesterol (LDL-C) levels. Methods and results The direct binding between PCSK9 and CAP1 was confirmed by immunoprecipitation assay, far-western blot, biomolecular 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 CAP1 as a new binding partner of PCSK9 and a key mediator of caveolae-dependent endocytosis and lysosomal degradation of LDLR.