Adenylyl Cyclase-Associated Protein 1 Is a Receptor for Human Resistin and Mediates Inflammatory Actions of Human Monocytes

• DOI: 10.1016/j.cmet.2014.01.013
• Publication Date: 2014-03-04T23:34:37Z
• Authors: Sahmin Lee; Hyun-Chae Lee; Yoo-Wook Kwon; Sang Eun Lee; Youngjin Cho; Joonoh Kim; Soobeom Lee; Ju-Young Kim; Jaewon Lee; Han-Mo Yang; Inhee Mook-Jung; Ky-Youb Nam; Junho Chung; Mitchell A. Lazar; Hyo-Soo Kim
• Keywords: Physiology; Molecular Sequence Data; Cell Cycle Proteins; Mice, Transgenic; Molecular Dynamics Simulation; Monocytes; Cell Line; Mice; 03 medical and health sciences; Cyclic AMP; Animals; Humans; Resistin; Amino Acid Sequence; Molecular Biology; 0303 health sciences; NF-kappa B; Cell Biology; Recombinant Proteins; Protein Structure, Tertiary; 3. Good health; Cytoskeletal Proteins; HEK293 Cells; Cytokines; Protein Binding; Signal Transduction

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.