We have shown that many proteins involved in the immune response and cancer contain ancient complexes of iron and sulfur, or iron-sulfur ([FeS]) clusters. The clusters in these proteins perform catalytic functions and act as sensors of reactive signalling species such as H2O2 or NO. One such protein is human SAND (also known as RSAD2). SAND expression restricts viral replication, regulates T cell function, and is linked to poor CAR T-cell persistence in patients. However, the mechanism by which SAND regulates T cell function is unknown. Elucidating the function of SAND in immune cells will reveal new antiviral drug targets and help discover new therapeutic approaches to treat viral infections or cancer. These studies are timely because of the continuous threat caused by the emergence and re-emergence of new strains of viruses like SARS-CoV-2 and the significant global health burden of infection-associated cancer.
Based on our recent discoveries, this project aims to elucidate how SAND regulates T regulatory (Tregs) cells function. The project has three specific objectives:
Year 1. Elucidate how pro-inflammatory and anti-inflammatory stimuli modulate SAND expression
Year 1-3. Identify protein partners of SAND in Tregs and elucidate their interaction using NMR spectroscopy and/or X-ray crystallography
Years 1-3. Establish the role of SAND in modulating central carbon metabolism
Years 2-4. Investigate the interaction of SAND’s [FeS] cluster with different reactive signalling molecules like H2O2 and NO.
To address these questions, we will use a multidisciplinary approach combining various techniques, including cell biological, biochemical assays, immunoprecipitation and western blot, NMR spectroscopy in collaboration with Prof Simone Ciofi-Baffoni (CERM, Italy), and metabolomics studies in collaboration with Prof James McCullagh (Department of Chemistry, University of Oxford).