Nucleic Acid Detection in Anti-Viral Responses and Autoimmunity

Viruses infect all living organisms. Therefore, hosts evolved extensive means to detect and destroy viral pathogens. Pattern recognition receptors that detect viral RNA or DNA genome are important components of the innate immune response against viruses. In vertebrates, viral nucleic acid is detected by two mechanisms that both result in the production of antiviral type I IFN. The first mechanism involves toll-like receptor detection of non-cell autonomous viral nucleic acid and allows uninfected, specialized innate immune cells to initiate an adaptive immune response to eliminate infection. Second, cell intrinsic receptors allow all infected cells to detect viral infection and induce a type I IFN response. The interferon stimulatory DNA (ISD) pathway specifically detects of viral DNA genomes. Chronic activation of the ISD pathway is the cause of lethal autoimmune disease in Trex1 deficient mice and humans thereby coupling innate immune detection to initiation of autoimmunity. The ISD pathway induces type I IFN by STING-dependent activation of TBK1 and IRF3. However, little is known about the DNA sensors proteins of the ISD pathway. Here we use the novel model of Trex1 autoimmunity to identify Trex1 interacting proteins that may be involved in ISD sensing. We discovered that Trex1 is localized to the inner nuclear membrane in addition to the endoplasmic reticulum and interacts with nuclear partners Brd7, Btf3l4, Chaf1a, Pias1, Rfc2 and Sae2. This data implies that negative regulation of the ISD pathway may occur in the nucleus and not the cytoplasm as previously thought. In addition, we identified new members and characterized the 13 members of the AIM2-like receptor (ALR) family of ISD sensors. Here we show the ALR family of nuclear proteins is highly divergent across mammals reflecting each species' unique struggle with specific viral pathogens. We also discovered the ALR proteins fit into two functional categories based on their ability to interact with STING and induce type I IFN or interact with ASC to activate the IL-1β inflammasome. Together our data imply nuclear detection of DNA occurs utilizing highly species-specific sensors and provides a functional framework for further study of the ISD sensors.