A fundamental question in immunology is how host defenses are initiated in response to specific microbial ligands particularly nucleic acids. Distint adapter molecules mediate signaling from a number of different classes of innate immune receptors to turn on activation of NF-?B and IRFs which in turn regulate expression of inflammatory cytokines, chemokines and anti-viral type I IFNs. TANK-binding kinase (TBK1) is a central signaling hub in nucleic acid sensing pathways. Tremendous progress has been made in understanding how TRIF and MAVS relay signaling from TLRs and RLRs to activate TBK1. Much less well understood is how DNA sensors activate TBK1. DNA sensing is important in a growing number of infectious diseases and is also central to the pathogenesis ofautoimmune diseases such as Systemic Lupus Erythematosis. An ER resident protein STING, has emerged as a key mediator of DNA driven type I IFN signaling. Understanding how TBK1 is activated by STING and how TBK1 regulates IRF-dependent as well as the recently identified STAT6-dependent target gene expression is very poorly understood. This renewal application will expand on our studies of TBK1 signaling and explore the hypothesis that TBK1 is a major component of the innate immune response to infection whereby TBK1 acts to relay signaling downstream of STING to engage IRFs and/or STAT6 to turn on expression of type I IFNs, ISGs and STAT6-regulated chemokines. In addition to immune response genes, we have found that non-coding regulatory RNAs called LincRNAs are also targets of TBK1 signaling pathways. LincRNAs are highly inducible upon infection or treatment with ligands of TLRs, RLRs and DNA sensing pathways. These LincRNAs in turn play an integral role in the regulation of innate immune signaling.
Aim -1 of this proposal will determine the molecular mechanisms for STING-dependent TBK1 activation using DMXAA, an anti-cancer drug as an activator of this pathway. In a second aim we will define the role of CNBP (cellcular nucleic acid binding protein), a proteinwe identified following Mass Spectrometry analysis of TBK1 complexes. The role of CNBP in orchestrating TBK1- dependent innate signaling will be studied in detail. Finally, in a third serie of experiments, we will characterize the induction and function of interferon inducible LincRNAs in regulation of innate immune signaling. Collectively, these studies will enhance our understanding of TBK1 signaling and unveil key new targets for therapeutic manipulation of infections and autoimmune diseases. Additionally, understanding TBK1 signaling also has broad implications for vaccine design.
TANK binding kinase-1 is a central component of the signaling pathways involved in the innate immune system. Understanding how TBK1 is activated is important for improving our understanding of the immune response to infection. Additionally, since innate immune signaling is often inadvertently activated by our own nucleic acids, TBK1 signaling can contribute to autoimmune diseases such as Lupus. The studies proposed in this application will enhance our understanding of TBK1 signaling and will unveil new mechanisms which we could in the future interfere with for the treatment of not only infectious but also autoimmune diseases. Additionally, understanding TBK1 signaling also has broad implications for vaccine design since innate immune signaling can be harnessed to improve vaccine effectiveness.
|Atianand, Maninjay K; Hu, Wenqian; Satpathy, Ansuman T et al. (2016) A Long Noncoding RNA lincRNA-EPS Acts as a Transcriptional Brake to Restrain Inflammation. Cell 165:1672-1685|
|Elling, Roland; Chan, Jennie; Fitzgerald, Katherine A (2016) Emerging role of long noncoding RNAs as regulators of innate immune cell development and inflammatory gene expression. Eur J Immunol 46:504-12|
|Baum, Rebecca; Sharma, Shruti; Carpenter, Susan et al. (2015) Cutting edge: AIM2 and endosomal TLRs differentially regulate arthritis and autoantibody production in DNase II-deficient mice. J Immunol 194:873-7|
|Chan, Jennie; Atianand, Maninjay; Jiang, Zhaozhao et al. (2015) Cutting Edge: A Natural Antisense Transcript, AS-IL1?, Controls Inducible Transcription of the Proinflammatory Cytokine IL-1?. J Immunol 195:1359-63|
|Pawaria, Sudesh; Moody, Krishna L; Busto, Patricia et al. (2015) An unexpected role for RNA-sensing toll-like receptors in a murine model of DNA accrual. Clin Exp Rheumatol 33:S70-3|
|Blin, Juliana; Fitzgerald, Katherine A (2015) Perspective: The RNA exosome, cytokine gene regulation and links to autoimmunity. Cytokine 74:175-80|
|Narayan, Kavitha; Waggoner, Lisa; Pham, Serena T et al. (2014) TRIM13 is a negative regulator of MDA5-mediated type I interferon production. J Virol 88:10748-57|
|Woo, Seng-Ryong; Fuertes, Mercedes B; Corrales, Leticia et al. (2014) STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41:830-42|
|Severa, Martina; Islam, Sabina A; Waggoner, Stephen N et al. (2014) The transcriptional repressor BLIMP1 curbs host defenses by suppressing expression of the chemokine CCL8. J Immunol 192:2291-304|
|Liehl, Peter; Zuzarte-Luís, Vanessa; Chan, Jennie et al. (2014) Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection. Nat Med 20:47-53|
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