Deng Zihou, Ma Shixin, Zhou Hao, Zang Aiping, Fang Yiyuan, Li Tiantian, Shi Huanjing, Liu Mei, Du Min, Taylor Patricia R, Zhu Helen He, Chen Jiangye, Meng Guangxun, Li Fubin, Chen Changbin, Zhang Yan, Jia Xin-Ming, Lin Xin, Zhang Xiaoming, Pearlman Eric, Li Xiaoxia, Feng Gen-Sheng, Xiao Hui
Key Laboratory of Molecular Virology and Immunology, Vaccine Center, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Nat Immunol. 2015 Jun;16(6):642-52. doi: 10.1038/ni.3155. Epub 2015 Apr 27.
Fungal infection stimulates the canonical C-type lectin receptor (CLR) signaling pathway via activation of the tyrosine kinase Syk. Here we identify a crucial role for the tyrosine phosphatase SHP-2 in mediating CLR-induced activation of Syk. Ablation of the gene encoding SHP-2 (Ptpn11; called 'Shp-2' here) in dendritic cells (DCs) and macrophages impaired Syk-mediated signaling and abrogated the expression of genes encoding pro-inflammatory molecules following fungal stimulation. Mechanistically, SHP-2 operated as a scaffold, facilitating the recruitment of Syk to the CLR dectin-1 or the adaptor FcRγ, through its N-SH2 domain and a previously unrecognized carboxy-terminal immunoreceptor tyrosine-based activation motif (ITAM). We found that DC-derived SHP-2 was crucial for the induction of interleukin 1β (IL-1β), IL-6 and IL-23 and anti-fungal responses of the TH17 subset of helper T cells in controlling infection with Candida albicans. Together our data reveal a mechanism by which SHP-2 mediates the activation of Syk in response to fungal infection.
真菌感染通过酪氨酸激酶Syk的激活刺激经典C型凝集素受体（CLR）信号通路。在此，我们确定了酪氨酸磷酸酶SHP-2在介导CLR诱导的Syk激活中的关键作用。在树突状细胞（DCs）和巨噬细胞中敲除编码SHP-2的基因（Ptpn11；此处称为“Shp-2”）会损害Syk介导的信号传导，并消除真菌刺激后编码促炎分子的基因的表达。从机制上讲，SHP-2作为一种支架，通过其N-SH2结构域和一个以前未被识别的基于酪氨酸的羧基末端免疫受体激活基序（ITAM），促进Syk募集到CLR去整合素-1或衔接蛋白FcRγ。我们发现，DC衍生的SHP-2对于诱导白细胞介素1β（IL-1β）、IL-6和IL-23以及辅助性T细胞TH17亚群在控制白色念珠菌感染中的抗真菌反应至关重要。我们的数据共同揭示了一种机制，通过该机制SHP-2介导对真菌感染的Syk激活。
