Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, 40225, Düsseldorf, Germany.
Institute of Molecular Medicine II, Medical Faculty, Heinrich-Heine-University, 40225, Düsseldorf, Germany.
Nat Commun. 2018 May 23;9(1):2034. doi: 10.1038/s41467-018-04454-8.
Cytokine-induced signal transduction is executed by natural biological switches, which among many others control immune-related processes. Here, we show that synthetic cytokine receptors (SyCyRs) can induce cytokine signaling using non-physiological ligands. High-affinity GFP- and mCherry-nanobodies were fused to transmembrane and intracellular domains of the IL-6/IL-11 and IL-23 cytokine receptors gp130 and IL-12Rβ1/IL-23R, respectively. Homo- and heterodimeric GFP:mCherry fusion proteins as synthetic cytokine-like ligands were able to induce canonical signaling in vitro and in vivo. Using SyCyR ligands, we show that IL-23 receptor homodimerization results in its activation and IL-23-like signal transduction. Moreover, trimeric receptor assembly induces trans-phosphorylation among cytokine receptors with associated Janus kinases. The SyCyR technology allows biochemical analyses of transmembrane receptor signaling in vitro and in vivo, cell-specific activation through SyCyR ligands using transgenic animals and possible therapeutic regimes involving non-physiological targets during immunotherapy.
细胞因子诱导的信号转导是由天然生物开关执行的，这些开关控制着许多与免疫相关的过程。在这里，我们表明，合成细胞因子受体（SyCyRs）可以使用非生理配体诱导细胞因子信号。高亲和力 GFP 和 mCherry 纳米体分别融合到 IL-6/IL-11 和 IL-23 细胞因子受体 gp130 和 IL-12Rβ1/IL-23R 的跨膜和细胞内结构域。同型和异型 GFP:mCherry 融合蛋白作为合成细胞因子样配体能够在体外和体内诱导经典信号。使用 SyCyR 配体，我们表明 IL-23 受体同二聚体导致其激活和 IL-23 样信号转导。此外，三聚体受体组装诱导相关 Janus 激酶之间的细胞因子受体的转磷酸化。SyCyR 技术允许在体外和体内进行跨膜受体信号的生化分析，使用转基因动物通过 SyCyR 配体进行细胞特异性激活，并在免疫治疗期间涉及非生理靶标进行可能的治疗方案。
