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Cyclase-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

Authors
 Hyun-Duk Jang  ;  Sang Eun Lee  ;  Jimin Yang  ;  Hyun-Chae Lee  ;  Dasom Shin  ;  Hwan Lee  ;  Jaewon Lee  ;  Sooryeonhwa Jin  ;  Soungchan Kim  ;  Seung Ji Lee  ;  Jihye You  ;  Hyun-Woo Park  ;  Ky-Youb Nam  ;  Sang-Hak Lee  ;  Sahng Wook Park  ;  Jin-Soo Kim  ;  Sang-Yeob Kim  ;  Yoo-Wook Kwon  ;  Soo Heon Kwak  ;  Han-Mo Yang  ;  Hyo-Soo Kim 
Citation
 EUROPEAN HEART JOURNAL, Vol.41(2) : 239-252, 2020-01 
Journal Title
 EUROPEAN HEART JOURNAL 
ISSN
 0195-668X 
Issue Date
2020-01
Keywords
Caveolae ; Cyclase-associated protein 1 ; Endocytosis ; LDL cholesterol ; Low-density lipoprotein receptor ; Proprotein convertase subtilisin/kexin type-9
Abstract
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.
Files in This Item:
T202001555.pdf Download
DOI
10.1093/eurheartj/ehz566
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Park, Sahng Wook(박상욱) ORCID logo https://orcid.org/0000-0002-9594-7074
Lee, Sang Hak(이상학) ORCID logo https://orcid.org/0000-0002-4535-3745
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/176175
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