Viral Mediated Type I Interferon Induction

摘要 这项研究提案的长期目标是确定负责重要 肿瘤坏死因子受体相关因子3（TRAF 3）和NF-κB诱导激酶（NIK）在调节宿主 防御病毒感染和自身免疫反应。我们在20多年前就确定了TRAF 3， 与包括CD 40、BAFFR和LTβR在内的TNF受体亚群相关的衔接分子。我们 随后产生的TRAF 3敲除小鼠，发现它们在出生后两周内死亡， 炎症反应。在过去的几年里，我们已经定义了一个TRAF/cIAP/NIK复合体， 负责通过组成性降解抑制未受刺激细胞中的非经典NF-κB活性 尼克我们发现的重要性得到了以下观察结果的支持： TRAF/cIAP/NIK复合物的组分与炎性和自身免疫性疾病相关， 以及几种血液癌症，如多发性骨髓瘤和弥漫性B细胞淋巴瘤。我们最近 研究还发现了一种新的NIK/IKK/CRL蛋白复合物，其作为负反馈控制 防止受体激活后过度反应的非经典NF-κB活性。此外，我们的初步 研究已经鉴定了一种新的NIK/STING/TBK 1复合物，其可以增强DNA诱导的I型干扰素 （IFN-I）生产。基于我们的遗传和生化研究，我们发现TRAF 3在 调节DNA相对于RNA诱导的IFN-1诱导。我们已经提供了证据，非- 经典的NF-κB和IFN-Ⅰ诱导通路不仅在调节宿主防御中起重要作用， 抗DNA病毒感染，而且在DNA和BAFF介导的IFN-I和自体免疫的协同生产中， 抗体，这是某些自身免疫性疾病，如狼疮的标志。我们的总体假设是 TRAF 3和NIK在调节抗病毒免疫和自身免疫应答中发挥重要作用， 控制非典型NF-κB活化及其与IFN-1产生的串扰。我们的目标是获得 TRAF 3和NIK在调节非经典NF-κB活化中的功能和机制的理解， IFN-I生产。在目标1中，我们将定义NIK/IKK/CRL复合物的主要成分，并确定 它们在非经典NF-κB通路的负反馈控制中的作用。在目标2中，我们将定义 NIK/STING/TBK 1复合物的主要成分，并确定它们在调节串扰中的作用 非经典NF-κB和IFN-I诱导途径之间的关系。在目标3中，我们将确定 非经典NF-κB活化与IFN-Ⅰ应答在宿主防御DNA病毒中相互作用 感染及其与自身免疫性疾病的关系。最后，我们将探讨使用小 非典型NF-κB途径的分子调节剂作为保护病毒感染和治疗 自身免疫性疾病我们相信，我们提出的研究将有助于未来的努力， 预防传染病和自身免疫性疾病。

ABSTRACT The long term goal of this research proposal is to determine the mechanisms responsible for the important functions of TNF receptor associated factor 3 (TRAF3) and NF-κB inducing kinase (NIK) in regulating host defense against viral infections and autoimmune responses. We identified TRAF3 over 20 years ago as an adaptor molecule associated with a subset of TNF receptors including CD40, BAFFR and LTβR. We subsequently generated TRAF3 knockout mice and found that they die within two weeks after birth with over- reactive inflammatory responses. In the past several years, we have defined a TRAF/cIAP/NIK complex responsible for suppressing non-canonical NF-κB activity in unstimulated cells through constitutively degrading NIK. The significance of our findings is supported by the observation that mutations in the genes encoding components of the TRAF/cIAP/NIK complex are associated with inflammatory and autoimmune diseases, as well as several hematological cancers such as multiple myeloma and diffuse B-cell lymphoma. Our recent studies have also discovered a novel NIK/IKK/CRL protein complex, which acts as a negative feedback control in preventing over-reactive non-canonical NF-κB activity after receptor activation. In addition, our preliminary studies have identified a novel NIK/STING/TBK1 complex, which can enhance DNA-induced Type I interferon (IFN-I) production. Based on our genetic and biochemical studies, we found TRAF3 has opposing roles in regulating DNA vs. RNA-induced IFN-I induction. We have provided evidence that crosstalk between the non- canonical NF-κB and IFN-I indcution pathways may play important roles not only in regulating host defense against DNA virus infection but also in DNA and BAFF-mediated syngergistic pruduction of IFN-I and auto- antibodies, which are a hallmark of certain autoimmune diseases such as Lupus. Our overall hypothesis is that TRAF3 and NIK play important roles in regulating anti-viral immunity and auto-immune responses through controlling non-canonical NF-κB activation and its crosstalk with IFN-I production. Our goal is to gain a functional and mechanistic understanding on TRAF3 and NIK in regulating non-canonical NF-κB activation and IFN-I production. In Aim 1, we will define the major components of the NIK/IKK/CRL complex and determine their roles in the negative feedback control of the non-canonical NF-κB pathway. In Aim 2, we will define the major components of the NIK/STING/TBK1 complex and determine their roles in regulating the crosstalk between non-canonical NF-κB and IFN-I induction pathways. In Aim 3, we will determine the contributions of the crosstalk between non-canonical NF-κB activation and IFN-I responses in host defense against DNA virus infections and its association with autoimmune diseases. Finally, we will explore the possibility of using small molecular regulators of the non-canonical NF-κB pathway as novel agents to protect viral infections and treat autoimmune diseases. We believe our proposed studies will assist in future attempts to pharmacologically intervene against infectious and autoimmune diseases.