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-?B 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 LT?R. 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-?B 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-?B 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-?B 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-?B 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-?B 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-?B 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-?B and IFN-I induction pathways.
In Aim 3, we will determine the contributions of the crosstalk between non-canonical NF-?B 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-?B 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.
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-?B inducing kinase (NIK) in regulating host defense against viral infections and autoimmune responses. Our studies will likely lead to new applications of certain ant-cancer drugs to treat infectious and autoimmune diseases.
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