Understanding the interaction of iRhoms and ADAM17

• Applicant: Dr. Astrid Elisabeth Evers
• Subject Area: Cell Biology ; Biochemistry ; Immunology ; Structural Biology
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 258166688

The main goal of this study is to understand, how the activity and the substrate selectivity of the metalloprotease ADAM17 are regulated. This enzyme cleaves a variety of cell surface molecules - a process called shedding. Even though ADAM17 is involved in several physiological and pathological events, it is still unknown how shedding is regulated and how the substrate selectivity is determined. Main substrates of ADAM17 are cytokines like TNFalpha - a key molecule in inflammation - and epidermal growth factor receptor (EGFR) ligands, which are essential for epithelial homeostasis. Therefore the role of ADAM17 in inflammation is ambivalent: On the one hand ADAM17 releases TNFalpha, which triggers the immune system and on the other hand it is essential for regeneration of epithelia after an immune response. To treat autoimmune or inflammatory diseases, it would be helpful to target ADAM17 in a very specific and tissue directed way.Lately a novel protein called iRhom2 was described to mediate the maturation of ADAM17 and therefore to regulate its activity. A close homolog of iRhom2 -iRhom1- was also shown to promote maturation of ADAM17. The interaction of iRhom2 and ADAM17 mainly plays a role in immune cells, because there is no endogenous iRhom1 expressed in these cells. Therefore loss of iRhom2 cannot be compensated by iRhom1 as shown in macrophages of iRhom2-knockout mice. Mature ADAM17 and shedding activity were missing exclusively in immune cells but not in other tissues, making iRhom2 a very attractive target for therapy of inflammatory diseases like Arthritis or Sepsis, where TNFalpha is the key player.In this project I aim to investigate the molecular mechanism of the interaction of iRhoms and ADAM17 by performing structural analyses of these proteins. Since there are reports pointing towards a role of iRhom2 not only in maturation but also in stimulated ADAM17 mediated shedding of distinct substrates, I want to analyze, if and how iRhoms regulate substrate selectivity of ADAM17.One main aspect of this project is to study the role of iRhoms in clinical mousemodells for Rheumatoid Arthritis, sepsis and angiogenesis - a process ADAM17 is also involved in. A particular mutant of iRhom2 called "sinecure" will be analyzed in this experiments, that will provide a better understanding of the relevance and the mechanism of this interaction.The detailled understanding of the interaction between ADAM17 and iRhom2 is necessary to develop new strategies for the therapeutic treatment of inflammatory diseases, that target iRhom2 and consequently ADAM17 activity .

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Carl Blobel, Ph.D.