Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland;
Finnish Institute of Occupational Health, 00250 Helsinki, Finland;
J Immunol. 2014 Jun 15;192(12):5952-62. doi: 10.4049/jimmunol.1303213. Epub 2014 May 7.
Dectin-1 is a membrane-bound pattern recognition receptor for β-glucans, which are the main constituents of fungal cell walls. Detection of β-glucans by dectin-1 triggers an effective innate immune response. In this study, we have used a systems biology approach to provide the first comprehensive characterization of the secretome and associated intracellular signaling pathways involved in activation of dectin-1/Syk in human macrophages. Transcriptome and secretome analysis revealed that the dectin-1 pathway induced significant gene expression changes and robust protein secretion in macrophages. The enhanced protein secretion correlated only partly with increased gene expression. Bioinformatics combined with functional studies revealed that the dectin-1/Syk pathway activates both conventional and unconventional, vesicle-mediated, protein secretion. The unconventional protein secretion triggered by the dectin-1 pathway is dependent on inflammasome activity and an active autophagic process. In conclusion, our results reveal that unconventional protein secretion has an important role in the innate immune response against fungal infections.
Dectin-1 是一种识别 β-葡聚糖的膜结合模式识别受体，β-葡聚糖是真菌细胞壁的主要成分。Dectin-1 识别 β-葡聚糖会引发有效的先天免疫反应。在这项研究中，我们采用系统生物学方法，首次全面描述了人巨噬细胞中激活 dectin-1/Syk 所涉及的分泌组和相关细胞内信号通路。转录组和分泌组分析表明，dectin-1 通路诱导了巨噬细胞中显著的基因表达变化和强大的蛋白质分泌。增强的蛋白质分泌仅与基因表达的增加部分相关。生物信息学结合功能研究表明，dectin-1/Syk 通路激活了常规和非常规的、囊泡介导的蛋白质分泌。dectin-1 通路触发的非经典蛋白质分泌依赖于炎症小体的活性和活跃的自噬过程。总之，我们的结果表明，非经典蛋白质分泌在针对真菌感染的先天免疫反应中起重要作用。
