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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56AI067497-06
Application #
8533490
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Leitner, Wolfgang W
Project Start
2006-03-01
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
6
Fiscal Year
2012
Total Cost
$415,209
Indirect Cost
$165,209
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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