Project ID CM-HD2023_11

ThemeCM-HD

Co Supervisor 1A School of Pharmaceutical ScienceWebsite

Co Supervisor 1B Comprehensive Cancer Centre, School of Pharmaceutical ScienceWebsite

Elucidating the Role of the antiviral iron-sulphur enzyme RSAD2in Tregsfunction and cancer

Background: RSAD2 (viperin) is an iron-sulphur [FeS] enzyme synthesising nucleotide analogue 3’-deoxy-3’,4’-didehydro-CTP (ddhCTP) . The protein expression is induced in response to viral infection and in many cancer cells (Human Protein Atlas). It restricts viral replication, regulates T cell function, and is linked to poor CAR T-cell persistence in patients. However, the mechanisms by which RSAD2 modules cancer growth and T cell function are unknown. We have discovered that RSAD2 activity alters central carbon metabolism and created RSAD2 knockout macrophages and cancer cell lines.

Hypothesis: Based on our findings, we hypothesis that RSAD2 activity supports tumour growth and regulates T cell function via different mechanism (Figure).

Methods and objectives: We will use a multidisciplinary approach combining cell biological and biochemical assays like 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). Our objectives are:

1. In year 1, Identify factors inducing RSAD2 expression in cancer and T cells
2. In years 1-3, Establish interactions of RSAD2 with known protein partners like galectin-9
3. In years 1-3, Establish the role of RSAD2 in modulating central carbon metabolism
4. In years 3-4, Investigate the role of RSAD2 in modulating lipid metabolism, angiogenesis, and redox state

Significance: Our past studies of RSAD2 revealed new antiviral molecules and future works are expected to help discover new therapeutics to treat viral infection or cancer. Thus, these studies are timely and will help counter future viral pandemics and the significant global health burden of infection-associated cancer.

One representative publication from each co-supervisor:

• Ebrahimi KH*, Diofi S, Hagedoorn PL, Nicolet Y, Le Brun NE, Hagen WR & Armstrong FA (2022) Iron-sulphur clusters as inhibitors and catalysts of viral replication. Nat Chem 14, 253–266.

• Treg sensitivity to FasL and relative IL-2 deprivation drive idiopathic aplastic anemia immune dysfunction. Lim SP, Costantini B, Mian SA, Perez Abellan P, Gandhi S, Martinez Llordella M, Lozano JJ, Antunes Dos Reis R, Povoleri GAM, Mourikis TP, Abarrategi A, Ariza-McNaughton L, Heck S, Irish JM, Lombardi G, Marsh JCW, Bonnet D, Kordasti S*, Mufti GJ. Blood. 2020 Aug 13;136(7):885-897. doi: 10.1182/blood.2019001347.
*Joint last author and corresponding author.