Quercetin targets the interaction of calcineurin with LxVP-type motifs in immunosuppression.
Calcineurin (CN) is a unique calcium/calmodulin (CaM)-activated serine/threonine phosphatase. To perform its diverse biological functions, CN communicates with many substrates and other proteins. In the physiological activation of T cells, CN acts through transcriptional factors belonging to the NFAT family and other transcriptional effectors. The classic immunosuppressive drug cyclosporin A (CsA) can bind to cyclophilin (CyP) and compete with CN for the NFAT LxVP motif. CsA has debilitating side effects, including nephrotoxicity, hypertension and tremor. It is desirable to develop alternative immunosuppressive agents. To this end, we first tested the interactions between CN and the LxVP-type substrates, including endogenous regulators of calcineurin (RCAN1) and NFAT. Interestingly, we found that quercetin, the primary dietary flavonol, can inhibit the activity of CN and significantly disrupt the associations between CN and its LxVP-type substrates. We then validated the inhibitory effects of quercetin on the CN-NFAT interactions in cell-based assays. Further, quercetin also shows dose-dependent suppression of cytokine gene expression in mouse spleen cells. These data raise the possibility that the interactions of CN with its LxVP-type substrates are potential targets for immunosuppressive agents.
Department of Biochemistry and Molecular Biology, Gene Engineering and Biotechnology Beijing Key Laboratory, Life Science Institute, Beijing Normal University, 100875 Beijing, China.
Yane
Y
Zhao
Department of Biochemistry and Molecular Biology, Gene Engineering and Biotechnology Beijing Key Laboratory, Life Science Institute, Beijing Normal University, 100875 Beijing, China.
Jin
J
Zhang
Department of Biochemistry and Molecular Biology, Gene Engineering and Biotechnology Beijing Key Laboratory, Life Science Institute, Beijing Normal University, 100875 Beijing, China.
Xiaoyu
X
Shi
Department of Biochemistry and Molecular Biology, Gene Engineering and Biotechnology Beijing Key Laboratory, Life Science Institute, Beijing Normal University, 100875 Beijing, China.
Jing
J
Li
Department of Biochemistry and Molecular Biology, Gene Engineering and Biotechnology Beijing Key Laboratory, Life Science Institute, Beijing Normal University, 100875 Beijing, China.
Rui
R
Wang
Department of Biochemistry and Molecular Biology, Gene Engineering and Biotechnology Beijing Key Laboratory, Life Science Institute, Beijing Normal University, 100875 Beijing, China.
Ruiwen
R
Song
Department of Biochemistry and Molecular Biology, Gene Engineering and Biotechnology Beijing Key Laboratory, Life Science Institute, Beijing Normal University, 100875 Beijing, China.
Qun
Q
Wei
Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Huaibin
H
Cai
Department of Biochemistry and Molecular Biology, Gene Engineering and Biotechnology Beijing Key Laboratory, Life Science Institute, Beijing Normal University, 100875 Beijing, China. Electronic address: luojing@bnu.edu.cn.
Jing
J
Luo
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D019703:Calcineurin / Q000737:chemistry / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D050778:NFATC Transcription Factors / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D011794:Quercetin / Q000494:pharmacology*
D016207:Cytokines; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D011794:Quercetin; D019703:Calcineurin
Calcineurin; Cyclosporine A; Cytokine expression; LxVP-motif; NFAT; Quercetin; RCAN1