Department of Pharmaceutical Sciences, University of Vienna, Vienna, Austria.
Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.
Elife. 2023 Feb 20;12:e69415. doi: 10.7554/eLife.69415.
Glycan-binding proteins, so-called lectins, are exposed on mammalian cell surfaces and decipher the information encoded within glycans translating it into biochemical signal transduction pathways in the cell. These glycan-lectin communication pathways are complex and difficult to analyze. However, quantitative data with single-cell resolution provide means to disentangle the associated signaling cascades. We chose C-type lectin receptors (CTLs) expressed on immune cells as a model system to study their capacity to transmit information encoded in glycans of incoming particles. In particular, we used nuclear factor kappa-B-reporter cell lines expressing DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN), macrophage C-type lectin (MCL), dectin-1, dectin-2, and macrophage-inducible C-type lectin (MINCLE), as well as TNFαR and TLR-1&2 in monocytic cell lines and compared their transmission of glycan-encoded information. All receptors transmit information with similar signaling capacity, except dectin-2. This lectin was identified to be less efficient in information transmission compared to the other CTLs, and even when the sensitivity of the dectin-2 pathway was enhanced by overexpression of its co-receptor FcRγ, its transmitted information was not. Next, we expanded our investigation toward the integration of multiple signal transduction pathways including synergistic lectins, which is crucial during pathogen recognition. We show how the signaling capacity of lectin receptors using a similar signal transduction pathway (dectin-1 and dectin-2) is being integrated by compromising between the lectins. In contrast, co-expression of MCL synergistically enhanced the dectin-2 signaling capacity, particularly at low-glycan stimulant concentration. By using dectin-2 and other lectins as examples, we demonstrate how signaling capacity of dectin-2 is modulated in the presence of other lectins, and therefore, the findings provide insight into how immune cells translate glycan information using multivalent interactions.
糖结合蛋白，即所谓的凝集素，暴露在哺乳动物细胞表面，解析糖链中编码的信息，并将其转化为细胞内的生化信号转导途径。这些糖-凝集素通讯途径复杂且难以分析。然而，具有单细胞分辨率的定量数据提供了分离相关信号级联的手段。我们选择表达在免疫细胞上的 C 型凝集素受体 (CTL) 作为模型系统，研究它们传递外来颗粒糖链中编码信息的能力。特别是，我们使用核因子 kappa-B-报告细胞系表达树突状细胞特异性 ICAM-3 抓取非整联蛋白 (DC-SIGN)、巨噬细胞 C 型凝集素 (MCL)、dectin-1、dectin-2 和巨噬细胞诱导型 C 型凝集素 (MINCLE)，以及单核细胞系中的 TNFαR 和 TLR-1&2，并比较它们传递糖编码信息的能力。除了 dectin-2 之外，所有受体都以相似的信号转导能力传递信息。这种凝集素在信息传递方面的效率明显低于其他 CTLs，即使通过过表达其共受体 FcRγ 来增强 dectin-2 途径的敏感性，其传递的信息也没有增强。接下来，我们将研究扩展到整合包括协同凝集素在内的多个信号转导途径，这在病原体识别过程中至关重要。我们展示了使用相似信号转导途径（dectin-1 和 dectin-2）的凝集素受体如何通过凝集素之间的折衷来整合信号转导能力。相比之下，MCL 的共表达协同增强了 dectin-2 的信号转导能力，尤其是在低聚糖刺激浓度下。通过使用 dectin-2 和其他凝集素作为示例，我们展示了 dectin-2 的信号转导能力如何在存在其他凝集素的情况下被调节，因此，这些发现为免疫细胞如何使用多价相互作用来翻译糖信息提供了深入的了解。
