Working Groups

The activities of these working groups collectively aim to bridge the research in iron-sulphur proteins, immunology, virology, and medicinal chemistry. They aim to develop new research ideas and collaborative projects with an emphasis on supporting early career investigators to develop their expertise and network.

Working Group 1 (WG1)

FeS clusters and FeS proteins serve both catalytic and structural roles in a range of biological and metabolic processes yet their role in the development, maturation and function of immune cells remains enigmatic. As our understanding of the rapidly emerging field of immunometabolism expands, we are now beginning to appreciate that FeS containing proteins are essential for the correct functioning of key metabolic pathways (e.g., glycolysis, fatty acid oxidation, the tricarboxylic acid cycle, etc.) engaged by naïve and effector immune cells of both the innate and adaptive immune system. However, little is known about the regulation of FeS cluster biology during the response of immune cells to viral or bacterial infections or the role of FeS containing proteins in the development and maturation of immune cells.

This WG aims to study the cellular function of FeS clusters and proteins in the immune response with a focus on:

How FeS enzymes or FeS biogenesis processes are altered in macrophages or other immune cells in response to infection?
Does the FeS biogenesis machinery support and control metabolic plasticity in macrophages and other immune cells in their naïve state or in response to viral or bacterial infections?
The role of FeS proteins in the development, differentiation, or maturation of immune cells.

Working Group 2 (WG2)

Recently evidence has been provided that certain viral proteins incorporate FeS clusters to support the viral life-cycle, and that human (or other host) cellular FeS proteins are required for the reproduction of viruses. For example the RNA dependent RNA polymerase of SARS-CoV2 (coronavirus) has been shown to contain two FeS clusters. This knowledge offers great opportunities for finding new therapeutic targets against viral infection and replication. Therefore it is important to understand how viral proteins obtain FeS clusters from the host, and what the involvement of such mechanisms is in the viral replication pathway. In order to achieve this level of understanding WG2 will support the following research: 1) investigation of the interaction of viral FeS protein with the host FeS biogenesis machinery, 2) study of viral FeS proteins, 3) study maturation of viral FeS proteins, 4) function of host FeS proteins in the viral life cycle, 5) establish protocols for this research. This will be done by participation in the COST action meetings and training activities, providing an expert network with this focus, build new collaborations and support short-term scientific missions on this topic.

Working Group 3 (WG3)

This Working Group is interested in the mechanistic studies of FeS cluster biogenesis using biochemical, biophysical, spectroscopic and structural approaches. Understand at a molecular level how iron, sulfur, electrons and protein dynamics work together to assemble an FeS cluster and transfer it to cellular target is fully exciting. The projects concerned are the FeS cluster assembly systems from E. coli (model) and from pathogens and the machineries involved in FeS assembly and transfer in eukaryotes during immune response to pathogens.

Working Group 4 (WG4)

Iron-sulfur cluster-containing proteins carry out a very wide range of functions in life, ranging from electron transfer and catalysis to gene regulation and sources of sulfur. Working Group 4 is focused on understanding the mechanisms by which iron-sulfur clusters carry out these functions. Mechanistic insight can be gained from both in vitro and in vivo approaches. In vitro work, usually with purified proteins, involves the application of a wide range of biophysical techniques, including spectroscopies (e.g. absorbance, CD, fluorescence, EPR, Mössbauer, resonance Raman, FT-IR, NRVS) structural methods (e.g. X-ray, NMR and cryo-EM), bioanalytical methods (ITC, SPR and AUC), various mass spectrometries (e.g. LC-MS, native MS), and rapid reaction kinetic methods. Studies of wild type and site-directed variants are often employed to determine residues that play important roles. In vivo work can also take many forms, such as gene knock out, complementation and/or expression studies, proteomics, metabolomics, and two-hybrid studies. The most powerful insights are typically gained from complementary in vitro and in vivo studies.

Working Group 5 (WG5)

FeS proteins play a central role in many cellular processes. They are emerging as targets for developing new therapeutics to treat human diseases with unmet needs like diabetes, cancer, and viral infection. MitoNEET is an example of FeS proteins that is a target of the thiazolidinedione diabetes drugs. Therefore, WG5 will offer tools and expertise in structural biology, medicinal chemistry, and computational chemistry to identify new drug targets and develop new therapeutic candidates. Examples of research topics that will be discussed include:

design and development of new antiviral nucleotide analogues mimicking the analogues produced by the antiviral and FeS enzyme RSAD2,
targeting FeS enzymes like RSAD1 to treat cancer, and
elucidating the mechanism of interaction of drugs with FeS proteins like MitoNEET