Séminaire CIRI (02.10.2023) : Dr. Stefan DÜSTERHÖFT

Stefan DÜSTERHÖFT, (University Hospital Aachen/ RWTH Aachen) :  « The iRhom-ADAM17 complex as a central regulator of inflammatory and growth factor signalling »               

Abstract: Membrane-anchored signalling mediators such as cytokines (e.g. TNFα) and many EGF receptor ligands (e.g. TGFa) as well as adhesion molecules are proteolytically released (shed) by the metalloproteinase ADAM17. Thus, ADAM17 plays a key role in many inflammatory and developmental processes. In addition, ADAM17 is an important step in the entry of viruses such as SARS-CoV and pestiviruses into cells. iRhom1 and iRhom2 are inactive members of the rhomboid protease family that are essential for the transport of ADAM17 to the cell surface as well as its regulation. However, the structure-function determinants and molecular regulation of the iRhom-ADAM17 complex are poorly understood. We are using bioinformatics (including A.I.-based structure modelling), molecular and cell biological as well as in vivo approaches to gain insight into the molecular mechanisms governing the functions and activity of the iRhom-ADAM17 complex. We have identified distinct regions in iRhom that are differentially responsible for iRhom functions and ADAM17 regulation, including binding, protein stability and protease activity. These mechanistic insights will form the basis for the development of methods to modify ADAM17 activity, which may be used to design novel therapeutic strategies against ADAM17-associated pathologies such as chronic inflammation and cancer.     

Hôte : Christiane Riedel