Negative regulation of C-type lectin receptor signaling in response to fungal infection

C 型凝集素受体信号传导对真菌感染的负调控

• 批准号: 9180678
• 负责人: MIEN-CHIE HUNG
• 金额: $ 40万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-11-13 至 2020-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9180678
• 关键词: Address; Affect; Antifungal Agents; Ants; Area; C Type Lectin Receptors; Cell physiology; Cells; Complex; Data; Down-Regulation; Event; Family; Genetic; Immune; Immune response; Immunity; Inflammatory; Innate Immune Response; Innate Immune System; Investigation; Lysosomes; MAPK8 gene; Mediating; Molecular; Mus; Mycoses; Nitric Oxide; Pattern recognition receptor; Play; Polyubiquitination; Process; Production; Proteins; Receptor Signaling; Recruitment Activity; Regulation; Resistance; Role; Signal Transduction; Testing; Therapeutic; Therapeutic Agents; Ubiquitination; antimicrobial; base; cytokine; design; inhibitor/antagonist; insight; killings; macrophage; mouse dectin-2; novel therapeutics; protective effect; public health relevance; receptor; receptor function; response; ubiquitin-protein ligase

 DESCRIPTION (provided by applicant): Emerging evidence indicates that several mammalian C-type lectin receptors (CLRs) in innate immune cells function as pattern recognition receptors (PRRs) for sensing fungal infections, and trigger multiple signaling cascades leading to expression of various pro- inflammatory cytokines and anti-microbial proteins. In our previous studies, we have found that Dectin-2 and Dectin-3, two CLRs, form a heterodimeric complex on innate immune cells and function as a PRR for sensing fungal infection. Although many studies have been focused on characterizing the activation event of CLR signaling in response to fungal infection, it is not very clear whether CLR proteins and their signaling are negatively regulated i response to fungal infection. In our preliminary studies, we have revealed two important aspects of negative regulation of CLR signaling. First, we found that Dectin-2 and Dectin-3, two CLRs involved in sensing fungal infection, were rapidly downregulated in macrophages following fungal challenging, and this downregulation is triggered by signal-induced ubiquitination through a Cbl- b-dependent mechanism, and the ubiquitinated Dectin-2/Dectin-3 appears to be degraded through a lysosome-mediated process. Second, we found that stimulation of Dectin-2/Dectin-3 can effectively induce JNK activation, but instead of playing a positive role, JNK1 activation negatively regulates CLR-induced CD23 expression that is involved in modulating anti-fungal immune response. Therefore, based on our compelling and exciting preliminary data, we propose 1) to determine the molecular mechanism by which Cbl-b regulates the degradation of Dectin-2/Dectin-3 in response to fungal infection; and 2) to characterize the molecular mechanism by which JNK1 is negatively involved in anti-fungal immune responses. Together, these lines of investigation will characterize two important mechanisms that negatively regulate host innate immune system against fungal infection, and will provide the molecular insight for designing novel therapeutic agents by modulating host innate immune system against fungal infection.

 描述（由申请人提供）：新出现的证据表明，先天免疫细胞中的几种哺乳动物C型凝集素受体（CLR）作为模式识别受体（PRR）起作用，用于感知真菌感染，并触发多个信号传导级联，导致各种促炎细胞因子和抗微生物蛋白的表达。在我们以前的研究中，我们已经发现Dectin-2和Dectin-3，两个CLR，在先天免疫细胞上形成异二聚体复合物，并作为PRR用于感测真菌感染。虽然许多研究都集中在表征真菌感染应答中的信号转导的激活事件，但不十分清楚真菌感染应答中的信号转导蛋白及其信号转导是否受到负调控。在我们的初步研究中，我们已经揭示了两个重要方面的负调控的信号转导。首先，我们发现，Dectin-2和Dectin-3，两种参与感知真菌感染的CLR，在真菌攻击后在巨噬细胞中迅速下调，并且这种下调是由信号诱导的泛素化通过Cbl-b依赖性机制触发的，并且泛素化的Dectin-2/Dectin-3似乎通过溶酶体介导的过程降解。其次，我们发现刺激Dectin-2/Dectin-3可以有效地诱导JNK活化，但JNK 1活化不是发挥积极作用，而是负性调节CLR诱导的CD 23表达，其参与调节抗真菌免疫应答。因此，基于我们令人信服和令人兴奋的初步数据，我们提出1）确定Cbl-b调节Dectin-2/Dectin-3降解以响应真菌感染的分子机制;和2）表征JNK 1负性参与抗真菌免疫应答的分子机制。总之，这些调查线将表征两个重要的机制，负调节宿主先天免疫系统对真菌感染，并将提供分子的见解，设计新的治疗药物，通过调节宿主先天免疫系统对真菌感染。