Research projects

The sphingolipid signaling pathway provides a response to cellular stress situations, starting from the hydrolysis of sphingomyelin by acid sphingomyelinase, yielding ceramide, and ultimately leading to apoptosis. Bacterial infection is an important cause of stress, arising from the interaction between the prokaryotic and eukaryotic cell, in which sphingolipids such as sphingomyelin and ceramide are being found to play a very important role. In the second year of this project, we focused our research on the cytokine interferon-gamma (IFN-γ). IFN-γ is a key regulator of innate and adaptive immunity involved in a large set of human diseases ranging from atherosclerosis to cancer. IFN-γ exerts its signaling effect by binding to a specific receptor localized in the cell plasma membrane named the interferon-gamma receptor (IFN-γR). We have investigated the role that bioactive lipids such as cholesterol (Chol), sphingolipids (SP), and phosphatidylcholine (PC), all of them abundant in the plasma membrane, have in IFN-γ activation. We first carried out in vivo photoaffinity experiments using radioactive and photoactivatable lipids, to characterize the binding of lipids to IFN-𝛾R in their native environment. We used bifunctional sphingosine (Sph), a lipid precursor of SP, bifunctional Chol, and PC.  Competition experiments were performed by administering separately to cells the bifunctional analogs and increasing amounts of the corresponding competing native lipids.  At this stage, we consider that we have deciphered the role that Chol plays in modulating cell surface IFN-𝛾R functions, and identified the IFN-𝛾R2TMD–Chol interaction as a potential drug target for the regulation of the IFN-𝛾/IFN-𝛾R1/IFN-𝛾R2/Chol signaling axis in a large number of diseases where IFN-𝛾 signaling is intimately involved.