E3 ubiquitin ligase Cbl-b negatively regulates C-type lectin receptor-mediated antifungal innate immunity.
E3 ubiquitin ligase Cbl-b negatively regulates C-type lectin receptor-mediated antifungal innate immunity.
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E3 泛素连接酶 Cbl-b 负向调节 C 型凝集素受体介导的抗真菌先天免疫。
DOI：
10.1084/jem.20151932
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发表时间：
2016-07-25
期刊：
影响因子：
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通讯作者：
Jia XM
中科院分区：
文献类型：
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作者：
Zhu LL;Luo TM;Xu X;Guo YH;Zhao XQ;Wang TT;Tang B;Jiang YY;Xu JF;Lin X;Jia XM
C型凝集素受体Dectin-2和Dectin-3介导的抗真菌感染的天然免疫应答受Cbl-b泛素化的负调控。各种C型凝集素受体(CLRs)的激活启动了对各种微生物感染的强烈的促炎反应。然而，激活的CLR是如何被负调控的仍不清楚。在这项研究中，我们报道了真菌感染激活CLR Dectin-2和Dectin-3，以Syk依赖的方式触发它们泛素化和降解。此外，我们还发现E3泛素连接酶Casitas B系淋巴瘤蛋白b(Cbl-b)通过接头蛋白Fcr-γ和酪氨酸激酶Syk相互作用来介导这些激活的CLR的泛素化，然后泛素化的CLR通过运输所需的内体分类复合体(ESCRT)系统被分类为溶酶体进行降解。因此，Cbl-b或ESCRT亚基的缺失显著降低了激活的CLR的降解，从而导致促炎细胞因子的高表达和炎症。与野生型对照相比，Cbl-b缺陷小鼠一贯对真菌感染具有更强的抵抗力。综上所述，我们的研究表明Cbl-b负性调节CLR介导的抗真菌天然免疫，这为设计抗真菌治疗药物提供了分子基础。
Innate immune responses mediated by C-type lectin receptors Dectin-2 and Dectin-3 against fungal infections are negatively regulated by Cbl-b ubiquitination. Activation of various C-type lectin receptors (CLRs) initiates potent proinflammatory responses against various microbial infections. However, how activated CLRs are negatively regulated remains unknown. In this study, we report that activation of CLRs Dectin-2 and Dectin-3 by fungi infections triggers them for ubiquitination and degradation in a Syk-dependent manner. Furthermore, we found that E3 ubiquitin ligase Casitas B–lineage lymphoma protein b (Cbl-b) mediates the ubiquitination of these activated CLRs through associating with each other via adapter protein FcR-γ and tyrosine kinase Syk, and then the ubiquitinated CLRs are sorted into lysosomes for degradation by an endosomal sorting complex required for transport (ESCRT) system. Therefore, the deficiency of either Cbl-b or ESCRT subunits significantly decreases the degradation of activated CLRs, thereby resulting in the higher expression of proinflammatory cytokines and inflammation. Consistently, Cbl-b–deficient mice are more resistant to fungi infections compared with wild-type controls. Together, our study indicates that Cbl-b negatively regulates CLR-mediated antifungal innate immunity, which provides molecular insight for designing antifungal therapeutic agents.