title: Adenylyl cyclase-associated protein 1 is a receptor for human resistin and mediates inflammatory actions of human monocytes.
abstract: Human resistin is a cytokine that induces low-grade inflammation by stimulating monocytes. Resistin-mediated chronic inflammation can lead to obesity, atherosclerosis, and other cardiometabolic diseases. Nevertheless, the receptor for human resistin has not been clarified. Here, we identified adenylyl cyclase-associated protein 1 (CAP1) as a functional receptor for human resistin and clarified its intracellular signaling pathway to modulate inflammatory action of monocytes. We found that human resistin directly binds to CAP1 in monocytes and upregulates cyclic AMP (cAMP) concentration, protein kinase A (PKA) activity, and NF-κB-related transcription of inflammatory cytokines. Overexpression of CAP1 in monocytes enhanced the resistin-induced increased activity of the cAMP-dependent signaling. Moreover, CAP1-overexpressed monocytes aggravated adipose tissue inflammation in transgenic mice that express human resistin from their monocytes. In contrast, suppression of CAP1 expression abrogated the resistin-mediated inflammatory activity both in vitro and in vivo. Therefore, CAP1 is the bona fide receptor for resistin leading to inflammation in humans.
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea; Department of Molecular Medicine & Biopharmaceutical Science, Graduate School of Convergence Science and Technology and College of Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea.
authors.forename: Sahmin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea.
authors.forename: Hyun-Chae
authors.initials: HC
authors.lastname: Lee
authors.affiliation: Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea.
authors.forename: Yoo-Wook
authors.initials: YW
authors.lastname: Kwon
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea.
authors.forename: Sang Eun
authors.initials: SE
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea.
authors.forename: Youngjin
authors.initials: Y
authors.lastname: Cho
authors.affiliation: Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea.
authors.forename: Joonoh
authors.initials: J
authors.lastname: Kim
authors.affiliation: Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea.
authors.forename: Soobeom
authors.initials: S
authors.lastname: Lee
authors.affiliation: Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea.
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea.
authors.forename: Jaewon
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea.
authors.forename: Han-Mo
authors.initials: HM
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea.
authors.forename: Inhee
authors.initials: I
authors.lastname: Mook-Jung
authors.affiliation: Bioinformatics & Molecular Design Research Center, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749, Korea; Gachon Institute of Pharmaceutical Sciences, Gachon University, 191 Hambakmoi-ro, Yonsu-gu, Incheon 406-813, Korea.
authors.forename: Ky-Youb
authors.initials: KY
authors.lastname: Nam
authors.affiliation: Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea.
authors.forename: Junho
authors.initials: J
authors.lastname: Chung
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, 12-102 Smilow Center for Translational Research, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea; Department of Molecular Medicine & Biopharmaceutical Science, Graduate School of Convergence Science and Technology and College of Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea; Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea. Electronic address: hyosoo@snu.ac.kr.
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D052243:Resistin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C489549:CAP1 protein, human; D018797:Cell Cycle Proteins; D016207:Cytokines; D003598:Cytoskeletal Proteins; D016328:NF-kappa B; D011994:Recombinant Proteins; D052243:Resistin; D000242:Cyclic AMP