Quercetin targets the interaction of calcineurin with LxVP-type motifs in immunosuppression

Yane Zhao, Jin Zhang, Xiaoyu Shi, Jing Li, Rui Wang, Ruiwen Song, Qun Wei, Huaibin Cai, Jing Luo

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)50-58
    Number of pages9
    JournalBiochimie
    Volume127
    DOIs
    StatePublished - Aug 1 2016

    Keywords

    • Calcineurin
    • Cyclosporine A
    • Cytokine expression
    • LxVP-motif
    • NFAT
    • Quercetin
    • RCAN1

    ASJC Scopus subject areas

    • Biochemistry

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