# Viral Mediated Type I Interferon Induction

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $385,000

## Abstract

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 belie...

## Key facts

- **NIH application ID:** 9873896
- **Project number:** 5R01AI069120-14
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** GENHONG CHENG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2006-04-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873896

## Citation

> US National Institutes of Health, RePORTER application 9873896, Viral Mediated Type I Interferon Induction (5R01AI069120-14). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9873896. Licensed CC0.

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