Controlling a novel catalytic center within an innate immune system protein to dampen or heighten the immune response.
Abstract
This application seeks to understand the novel molecular mechanisms of how an innate immune system protein dampens the immune response, with the ultimate goal of controlling innate immune responses. Interleukin I receptor associated kinase 3 (£RAK3) has key roles in suppressing the innate immune response and therefore maintaining homeostasis in inflammatory responses. We have identified a catalytic center within IRAK3 that generates small amounts of the signaling nucleotide, cyclic GMP (cGMP). The catalytic center within IRAK3 is conserved across vertebrate species. Our proof-of-concept experiments indicate that inactivation of the catalytic center decreases cGMP production and importantly also inhibits the ability of IRAK3 to suppress nuclear factor KB (NFKB) mediated inflammatory responses. In this application, we outline a series of experiments to explore how this novel catalytic function influences TRAK3 mediated intracellular interactions. Specifically, our objectives are to: ( I) define the essential elements of the catalytic site; (2) resolve the role of the various domains in the IRAK3 K3 protein scaffold; and (3) determine the GTP and cGMP binding kinetics of £RAK3. We also outline future directions to expand understanding of the function of IRAK3 within the cell following on from this proposal. Interrogating the novel mechanism of action of £RAK3 at the molecular level will inform our long term goal of controlling innate immune responses to permit or restrict infection. Ultimately, by understanding cellular permissive and non-permissive states to infection, improvements in therapeutic approaches to treat infection and disturbances in the immune state can be made.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- May 07, 2018
- Source ID
- W911NF1710303
Entities
People
- Helen R. Irving
Organizations
- Army Contracting Command
- Monash University
- United States Army