TRAF3 regulation in antiviral host defense

TRAF3在抗病毒宿主防御中的调控

• 批准号: 10727746
• 负责人: Kislay Parvatiyar
• 金额: $ 22.93万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-22 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727746
• 关键词: Age of Onset; B-Lymphocytes; Cell Maintenance; Cell Survival; Cells; Chromosomal Instability; Complex; DNA; DNA Damage; Data; Data Set; Development; Disease; Disparate; Event; Fostering; Goals; Homeostasis; Host Defense; Immune; Infection; Inflammatory; Inflammatory Response; Innate Immune Response; Interferon Activation; Interferon Type I; Licensing; Ligation; Link; Lymphoid; Natural Immunity; Nucleic Acids; Organogenesis; Pathway interactions; Pattern recognition receptor; Phosphotransferases; Play; Protein Kinase Interaction; Proteins; Publications; Publishing; RNA; Regulation; Regulatory Element; Research; Role; Signal Pathway; Signal Transduction; Sterility; Synaptosomes; TNF receptor-associated factor 3; Testing; Tumor Necrosis Factor Receptor; Viral; Viral Genes; Viral Genome; Virus Diseases; Virus Replication; age related; autoinflammatory; autoinflammatory diseases; combat; cytokine; extracellular; liquid chromatography mass spectrometry; member; nervous system disorder; novel; novel therapeutics; nucleic acid detection; prediction algorithm; programs; response; therapeutic target; transcription factor; viral detection

Project Summary The induction of type I interferon (IFN-I) cytokines plays an essential role in the innate immune response to virus infections by eliciting an antiviral gene program that facilitates the suppression of virus replication and spread. Cytosolic detection of viral nucleic acids by germ-line encoded pattern recognition receptors (PRRs) serves as an initial first step in activating the IFN-I response. Emerging studies however, have linked previously unknown roles for DNA sensing PRRs in detecting aberrant DNA species of self-origin to trigger the onset of age-related diseases, neurological disorders, and autoinflammatory conditions in the absence of infection. Thus, there is a critical need to delineate the mechanisms by which nucleic acid sensing PRRs control IFN-I activation to develop the next generation of therapeutics to combat viral infections as well as DNA damage driven disease states. We have recently identified a novel cross-talk phenomenon between cytosolic nucleic acid sensing PRRs that activate IFN-I and the non-canonical NF-κB pathway. While the non-canonical NF-κB pathway primarily governs lymphoid organogenesis and B-cell survival and maintenance in response to extracellular ligation of select members of the TNF receptor superfamily, our data unexpectedly revealed that intracellular ligation of nucleic acid sensing cytosolic PRRs also resulted in non-canonical NF-κB activation by causing the turnover of TNF receptor associated factor 3 (TRAF3), a key component of a steady-state negative regulatory complex that persistently causes the destabilization of the non-canonical NF-ĸB inducing kinase (NIK) which initiates signaling to the non-canonical NF-ĸB transcription factor complex. Our preliminary data further established that TRAF3 and NIK operate as differential regulators of IFN-I activation downstream of RNA and DNA sensing cytosolic PRRs. However, the mechanisms by which TRAF3 and NIK are controlled to modulate non-canonical NF-κB and IFN-I activation upon nucleic acid detection by cytosolic PRRs are poorly defined. Here we interrogated published data sets that examined TRAF3 and NIK protein interaction networks with a goal of identifying novel candidates with the potential to modulate how the non-canonical NF-κB pathway undergoes activation during cytosolic nucleic acid signaling and how the non-canonical NF-κB effector, NIK cross-talks with the IFN-I signaling platform. We identify synaptosome associated protein 29 (SNAP29) as a TRAF3 interacting partner and seek to characterize how SNAP29 modulates TRAF3 function in the context non-canonical NF-ĸB and IFN-I pathway activation. Our studies will help define new regulatory elements that control not only antiviral host defense programs, but also immune development and age related autoinflammatory disease states triggered by DNA damage or chromosomal instability.

项目摘要 I型干扰素（IFN-I）细胞因子的诱导在先天性免疫应答中起重要作用， 通过引发有助于抑制病毒复制的抗病毒基因程序， 传播.通过生殖系编码的模式识别受体（PRRs）检测病毒核酸的胞质 作为激活IFN-1应答的第一步。然而，新的研究表明， 以前未知的作用，DNA传感PRRs在检测异常的DNA种类的自我起源，以触发 年龄相关疾病、神经系统疾病和自身炎性疾病的发作， 感染因此，迫切需要描述核酸感测PRR的机制， 控制IFN-I的激活，以开发下一代治疗药物来对抗病毒感染和DNA 损害驱动的疾病状态。我们最近发现了一种新的细胞溶质之间的串扰现象， 激活IFN-1和非经典NF-κB途径的核酸感应PRR。而非典型的 NF-κB通路主要控制淋巴器官发生和B细胞存活和维持， TNF受体超家族的选择成员的细胞外连接，我们的数据出乎意料地揭示， 细胞内连接核酸感应胞质PRRs也导致非典型的NF-κB活化， 导致TNF受体相关因子3（TRAF 3）的周转，TRAF 3是稳态负调控的关键成分， 持续引起非典型NF-κ B诱导激酶不稳定的调节复合物 (NIK)其启动向非典型NF-κ B转录因子复合物的信号传导。我们的初步数据 进一步确定TRAF 3和NIK作为IFN-1激活下游的差异调节剂， RNA和DNA传感胞质PRR。然而，TRAF 3和NIK的控制机制， 在通过胞质PRR进行核酸检测时，调节非典型NF-κB和IFN-I活化的能力较差 定义了在这里，我们询问了研究TRAF 3和NIK蛋白相互作用网络的已发表数据集 目的是鉴定具有调节非经典NF-κB 在胞质核酸信号传导过程中，非经典NF-κB通路经历激活， NIK与IFN-I信号传导平台的交叉对话。我们鉴定出突触体相关蛋白29 SNAP 29作为TRAF 3相互作用的伴侣，并试图表征SNAP 29如何调节TRAF 3在肿瘤中的功能。 背景非经典NF-κ B和IFN-I途径活化。我们的研究将有助于确定新的监管 不仅控制抗病毒宿主防御程序，而且控制免疫发育和年龄相关的 由DNA损伤或染色体不稳定性引发的自身炎症性疾病状态。