한빛사논문
- 조회1,475
Hyun-Duk Jang1,2,3†, Sang Eun Lee4†, Jimin Yang1,2,3,5†, Hyun-Chae Lee1,2,3,5, Dasom Shin1,2,3,5, Hwan Lee1,2,3,5, Jaewon Lee1,2,3, Sooryeonhwa Jin1,2,3,5, Soungchan Kim1,2,3,5, Seung Ji Lee1,2,3,5, Jihye You1,2,3,5, Hyun-Woo Park1,2,3, Ky-Youb Nam6, Sang-Hak Lee7, SahngWook Park8, Jin-Soo Kim9, Sang-Yeob Kim10, Yoo-Wook Kwon1,2,3, Soo Heon Kwak11, Han-Mo Yang1,2,3,12, and Hyo-Soo Kim1,2,3,5,12*
1 National Leading Laboratory for Stem Cell Research, Seoul National University College of Medicine, 71, Daehak-Ro, Jongno-Gu, Seoul 03082, Korea; 2 Korea Research-Driven Hospital, Biomedical Research Institute, Seoul National University Hospital, 71, Daehak-ro, Jongro-gu, Seoul 03082, Korea; 3 Strategic Center of Cell & Bio Therapy, Seoul National University Hospital, 71, Daehak-ro, Jongro-gu, Seoul 03082, Korea; 4 Department of Cardiology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea; 5 Department of Molecular Medicine and Biopharmaceutical Sciences, World Class University Program, Seoul National University, Seoul 03082, Korea; 6 Bio AI Research Center, Pharos I&BT Co., Ltd., Anyang-si, Gyeonggi-do 14059, Korea; 7 Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, 134 Shinchon-Dong, Seodaemun-Gu, Seoul 120752, Korea; 8 Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120752, Korea; 9 Department of Chemistry, Seoul National University, Seoul 120752, Korea; 10 Department of Convergence Medicine, University of Ulsan College of Medicine and Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea; 11 Department of Internal Medicine, Seoul National University Hospital, 101, Daehak-Ro Jongno-Gu, Seoul 03080, Korea; and 12 Cardiovascular Center & Department of Internal Medicine, Seoul National University Hospital, 101, Daehak-Ro Jongno-Gu, Seoul 03080, Korea
† The first three authors contributed equally to this work.
* Corresponding author
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.
Keywords: Proprotein convertase subtilisin/kexin type-9, Low-density lipoprotein receptor, Cyclase-associated protein 1, LDL cholesterol, Endocytosis, Caveolae
논문정보
- Research article
- 2019년 08월 (BRIC 등록일 2019-08-26)
- 국내 연구진
- 의약학 > 응용의학
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