Functional characterization of CARD9 genetic variants in fungal immunity

CARD9 遗传变异在真菌免疫中的功能表征

• 批准号: 10331807
• 负责人: Ramnik J Xavier
• 金额: $ 69.83万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-08 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331807
• 关键词: Affect; Alleles; BCL10 gene; C Type Lectin Receptors; C-terminal; Candida; Carbohydrates; Cells; Chronic; Colitis; Communicable Diseases; Data; Dendritic Cells; Detection; Deubiquitination; Development; Disease; Disease susceptibility; Down-Regulation; Equilibrium; Exhibits; Gene Expression; Genes; Genetic Polymorphism; Genomics; Goals; Hereditary Disease; Host Defense; Human; Human Genetics; Immune; Immune response; Immunity; Individual; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Injury; Investigation; Life; Mediating; Minor; Molecular; Mucosa- associated lymphoid tissue lymphoma translocation protein-1; Mucous Membrane; Mutation; Mycoses; Natural Immunity; Patients; Penetrance; Persons; Phenotype; Phosphorylation; Population; Predisposition; Production; Receptor Signaling; Regulation; Reporting; Risk; Role; Sampling; Second Messenger Systems; Series; Signal Transduction; Signaling Protein; Skin; Splice-Site Mutation; Spondylitis; Surface; Systemic infection; Systems Biology; Ubiquitin; Ubiquitination; Work; congenital immunodeficiency; cytokine; disorder risk; experience; functional genomics; fungus; gene function; gene product; genetic variant; human disease; loss of function mutation; mouse model; novel; novel therapeutic intervention; pathogen; pathogenic fungus; promoter; protective allele; protein function; recruit; release of sequestered calcium ion into cytoplasm; response; small molecule; therapeutic target; tissue biomarkers

ABSTRACT Fungi are ubiquitous colonizers of skin and mucosal surfaces. While many individuals exhibit minor fungal outgrowth, millions of others experience systemic infections with life-threatening consequences. Polymorphisms in numerous genes have been associated with the ability of an individual to generate an inflammatory response to fungal pathogens. In many of these genes, rare high-penetrance alleles have been observed that strongly disrupt gene function, resulting in primary immunodeficiencies and an increase in infectious disease susceptibility. Additionally, common genetic variants have been reported in these genes that increase the risk of disease by modifying the activity or expression of the gene product to a small but significant degree. These genes offer a unique opportunity to understand how immune responses to pathogens are tuned to achieve an appropriate level of immune response. This hypothesis is well illustrated by the various phenotypes associated with different genetic variants of CARD9. CARD9 is a signaling protein that functions downstream of many C type lectin receptors (CLRs), which recognize carbohydrate moieties on fungi and other pathogens. Understanding how these human disease-related CARD9 mutations affect CARD9 functions will advance our understanding of fungal immunity. In Aim 1 of this proposal, we examine the role of Card9 ubiquitination on fungal detection by dendritic cells. In Aim 2, we will identify the molecular mechanisms controlling Card9 phosphorylation and their consequences for fungal detection. In Aim 3, we compare how Card9 genetic variants affect Candida infection and the development of colitis. Together, these aims will decipher the mechanistic basis of CARD9 regulation and characterize CARD9 genetic variants to identify novel molecular mechanisms with important roles in fungal defense and inflammation.

抽象的 真菌是皮肤和粘膜表面普遍存在的定植者。虽然许多人表现出轻微的真菌生长，但还有数百万人经历了全身感染，造成危及生命的后果。许多基因的多态性与个体对真菌病原体产生炎症反应的能力有关。在许多这些基因中，观察到罕见的高外显率等位基因会强烈破坏基因功能，导致原发性免疫缺陷和传染病易感性增加。此外，这些基因中已报道了常见的遗传变异，这些变异通过在小而显着的程度上改变基因产物的活性或表达来增加疾病风险。这些基因提供了一个独特的机会来了解如何调整对病原体的免疫反应以达到适当的免疫反应水平。与 CARD9 不同遗传变异相关的各种表型很好地说明了这一假设。 CARD9 是一种信号蛋白，在许多 C 型凝集素受体 (CLR) 下游发挥作用，CLR 识别真菌和其他病原体上的碳水化合物部分。了解这些与人类疾病相关的 CARD9 突变如何影响 CARD9 功能将增进我们对真菌免疫的理解。在该提案的目标 1 中，我们研究了 Card9 泛素化在树突状细胞检测真菌中的作用。在目标 2 中，我们将确定控制 Card9 磷酸化的分子机制及其对真菌检测的影响。在目标 3 中，我们比较了 Card9 基因变异如何影响念珠菌感染和结肠炎的发展。总之，这些目标将破译 CARD9 调控的机制基础，并表征 CARD9 遗传变异，以确定在真菌防御和炎症中具有重要作用的新分子机制。

项目成果

Tetraspanin CD82 Organizes Dectin-1 into Signaling Domains to Mediate Cellular Responses to Candida albicans.

四跨膜蛋白 CD82 将 Dectin-1 组织成信号传导域，以介导细胞对白色念珠菌的反应。

• 发表时间: 2019
• 作者: Tam, Jenny M;Reedy, Jennifer L;Lukason, Daniel P;Kuna, Sunnie G;Acharya, Mridu;Khan, Nida S;Negoro, Paige E;Xu, Shuying;Ward, Rebecca A;Feldman, Michael B;Dutko, Richard A;Jeffery, Jane B;Sokolovska, Anna;Wivagg, Carl N;Lassen, Kara G;Le Na
• 通讯作者: Le Na

Mediated Signaling - Lectin Receptor USP15 Deubiquitinates CARD9 to Downregulate C-Type

介导的信号传导 - 凝集素受体 USP15 去泛素化 CARD9 以下调 C 型

• DOI: 10.1155/2020/1438928
• 发表时间: 2024-09-13
• 期刊: BioMed Research International
• 作者: Wenting Xu;J. Rush;D. Graham;Zhifang Cao;R. Xavier
• 通讯作者: R. Xavier