Control of Dendritic Cell Function by the Lipopolysaccharide (LPS)-Responsive and Beige-like Anchor protein (Lrba)

脂多糖 (LPS) 响应性和米色样锚定蛋白 (Lrba) 对树突细胞功能的控制

• 批准号: 10214608
• 负责人: Emre Erol Turer
• 金额: $ 12.29万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-10 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214608
• 关键词: Address; Affect; Animals; Autoimmunity; Categories; Cell physiology; Cells; Chronic; Colitis; Data; Defect; Dendritic Cells; Dendritic cell activation; Development; Disease; Endocytosis; Endosomes; Essential Genes; Ethylnitrosourea; Etiology; Exhibits; Extracellular Matrix Proteins; FRAP1 gene; Gastrointestinal Diseases; Genes; Genetic Diseases; Genetic Screening; Genetic study; Goals; Growth Factor; Health Care Costs; Homeostasis; Human; Human Genetics; IRF3 gene; Immune; Immune signaling; Induced Mutation; Inflammation; Inflammatory Bowel Diseases; Innate Immune System; Interferon Type I; Interferons; Intestinal Diseases; Intestines; Knock-out; Knowledge; Lead; Lipopolysaccharides; Maintenance; Mass Spectrum Analysis; Mendelian disorder; Microbe; Molecular; Molecular Chaperones; Mouse Protein; Mus; Mutation; Nonsense Mutation; PI3K/AKT; Pathway interactions; Peripheral; Phagocytosis; Phagolysosome; Play; Predisposition; Production; Protein Deficiency; Proteins; Proteome; Receptor Signaling; Role; Signal Transduction; Sodium Dextran Sulfate; System; TLR3 gene; TLR7 gene; Tissues; Toll-like receptors; United States; Vesicle; Wild Type Mouse; Work; cell type; chemokine; cytokine; dextran sulfate sodium induced colitis; enteritis; experimental study; genetic signature; in vivo; inflammatory disease of the intestine; insight; intestinal epithelium; intestinal homeostasis; macrophage; pathogen; prevent; response; stressor; trafficking

Project Summary LRBA protein deficiency is a monogenic cause of autoimmunity and inflammatory bowel disease (IBD) in humans, but the basic cellular and molecular underpinnings responsible for the disease are not completely understood. In an ongoing forward genetic screen for N-ethyl-N-nitrosourea (ENU)-induced mutations that increase susceptibility to dextran sodium sulfate (DSS)-induced colitis in mice, we identified two nonsense mutations in Lrba. We found that dendritic cells (DCs) contribute significantly to intestinal inflammation in Lrba- deficient mice. In response to the stimulation of the Toll-like receptors (TLRs) TLR3, TLR7, and TLR9, Lrba- /- DCs exhibited excessive chemokine and type I interferon production as well as exaggerated IRF3/7- and PI3K/mTORC1-dependent signaling. Knockout of Unc93b1, a chaperone necessary for trafficking of TLR3, TLR7, and TLR9 to endosomes, caused a significant amelioration of the cytokine expression and colitis sensitivity after DSS treatment in Lrba-/- mice. Our data support a function for Lrba in restricting endosomal TLR signaling and subsequent intestinal inflammation. We propose to further elucidate the role of Lrba in innate immune cells in two interconnected and focused aims: Aim 1: To determine the role dendritic cell-intrinsic Lrba plays in experimental colitis. Aim 2: Elucidate the cellular trafficking defects of Lrba-/- dendritic cells that lead to exaggerated endosomal TLR responses. The aims in this proposal will help elucidate the mechanisms underlying the role of dendritic cells in tissue inflammation and the coordination of immune signaling within them.

项目摘要 LRBA蛋白缺乏是一个单基因的原因，自身免疫和炎症性肠病（IBD）， 人类，但负责疾病的基本细胞和分子基础并不完全 明白在一项正在进行的N-乙基-N-亚硝基脲（ENU）诱导突变的正向遗传筛查中， 增加小鼠对葡聚糖硫酸钠（DSS）诱导结肠炎的易感性，我们鉴定了两种无意义的 Lrba的突变。我们发现树突状细胞（DC）在Lrba的肠道炎症中起重要作用， 缺陷小鼠在Toll样受体（TLR）TLR3、TLR7和TLR9的刺激下，Lrba- /-DC表现出过度的趋化因子和I型干扰素产生以及过度的IRF3/7-和 PI3K/mTORC1依赖性信号传导。TLR3转运所必需的伴侣蛋白Unc93b1的敲除， TLR7和TLR9与内体的结合，引起细胞因子表达和结肠炎的显著改善。 Lrba-/-小鼠中DSS处理后的敏感性。我们的数据支持Lrba限制内体TLR的功能 信号传导和随后的肠道炎症。我们建议进一步阐明Lrba在先天性免疫缺陷中的作用。 免疫细胞在两个相互关联和集中的目标：目标1：确定树突状细胞的作用，内在Lrba 在实验性结肠炎中起作用目的2：阐明Lrba-/-树突状细胞的细胞运输缺陷，导致 夸大的内体TLR反应。本提案的目的将有助于阐明 树突状细胞在组织炎症中的作用以及它们内部免疫信号的协调。

项目成果

SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell-mediated immunity.

• DOI: 10.1126/science.aba4220
• 发表时间: 2021-05-14
• 期刊: Science (New York, N.Y.)
• 作者: Yue T;Zhan X;Zhang D;Jain R;Wang KW;Choi JH;Misawa T;Su L;Quan J;Hildebrand S;Xu D;Li X;Turer E;Sun L;Moresco EMY;Beutler B
• 通讯作者: Beutler B