Structural and functional insights into the role of Themis:SHP-1 complexes in inflammation

Lymphocyte development is tightly regulated to prevent the expansion of destructive, self-reactive T and B cells and the development of autoimmune and autoinflammatory diseases. Themis1, a T cell-specific protein, is a key regulator of thymocyte development. Accumulating evidence also links Themis to inflammatory diseases, such as rheumatoid arthritis, yet the structural and mechanistic basis of these pleiotropic functions remain poorly understood. Themis1, and the related protein Themis2, contain two copies of a newly described domain, dubbed the CABIT domain, crucial for Themis activity. The objective of this research program is to provide insights into the structure and function of Themis1 and Themis2, in complex with the phosphatase SHP-1, and to investigate the unexplored roles of Themis in inflammatory signalling and in vivo disease models. Characterization of Themis structural domains, particularly the CABIT domain, and how these proteins interact and modulate binding partners such as SHP-1 will provide timely insights into the function of CABIT domain-containing proteins in inflammatory pathways. We expect that this work will lead to a better understanding of Themis1 and related proteins and impact the development of novel therapeutic strategies to target Themis activity in inflammatory diseases.