Functions of novel phospholipase D proteins in nucleic acid sensing

项目摘要/摘要 这是一个R01项目，旨在研究磷脂酶D4(PLD4)在核酸传感中的作用。白细胞 携带保守的传感器，用于内吞的DNA和RNA，这些DNA和RNA可触发促炎因子的产生 细胞因子，包括I型干扰素。随之而来的炎症可能有利于宿主防御 微生物、病毒和肿瘤，但也可能是致病的，并可能阻碍潜在的 治疗性寡核苷酸。PLD4是一种溶酶体蛋白，其功能尚不清楚。全基因组 相关研究已将PLD4与人类类风湿性关节炎和系统性硬化症联系起来。我们发现 PLD4缺陷小鼠的表型与人类疾病巨噬细胞激活综合征相似， 通过反复注射Toll样受体9激动剂在小鼠身上模拟这种情况。在这里，我们测试 PLD4分解摄取的DNA和RNA并调节宿主防御和炎症的假说 通过促进TLR7、TLR8(在人类)和TLR8的核酸破坏和调节识别 TLR9.我们将描述PLD4缺乏如何促进MAS样表型，以及PLD4缺乏如何在 PLD4或PLD3+PLD4影响TLR7和TLR9对特定配体的反应，导致细胞因子改变 分泌物。还将评估PLD4在自我/非自我歧视中的可能作用。长期目标 其中一项研究是了解PLD4的基本生物学，它在宿主防御和炎症中的功能， 并为未来潜在的翻译研究奠定基础。

Project Summary/Abstract This is a R01 project to study the role of Phospholipase D4 (PLD4) in nucleic acid sensing. Leukocytes carry conserved sensors for endocytosed DNA and RNA that trigger the production of proinflammatory cytokines, including type I interferon. The ensuing inflammation can be beneficial for host defense to microorganisms, viruses, and tumors, but can also be pathogenic, and may thwart the use of potentially therapeutic oligonucleotides. PLD4 is a lysosomal protein whose function is not understood. Genome-wide association studies have linked PLD4 to human rheumatoid arthritis and systemic sclerosis. We find that PLD4-deficient mice have a phenotype similar to the human disease macrophage activation syndrome, which is mimicked in mice by repeated injections with Toll-like receptor 9 agonists. Here we test the hypotheses that PLD4 breaks down ingested DNA and RNA and regulates host defense and inflammation by promoting the destruction nucleic acids and regulating recognition by TLR7, TLR8 (in humans) and TLR9. We will characterize how PLD4 deficiency promotes a MAS-like phenotype and how deficiencies in PLD4 or PLD3+PLD4 affect TLR7 and TLR9 responses to specific ligands, leading to altered cytokine secretion. The possible role of PLD4 in self/nonself discrimination will also be assessed. The long-term goal of these studies is to understand the basic biology of PLD4, its functions in host defense and inflammation, and to develop a basis for potential future translational research.