Project title: Understanding the mechanism of the linear ubiquitin E3 ligase complex LUBAC
Summary: The linear ubiquitin assembly complex LUBAC is a ubiquitin E3 ligase with crucial roles in the initiation of the innate immune response and the activation of the NF-κB signaling pathway. Dysregulation of LUBAC is associated with autoinflammation, immunodeficiencies and the development of diffuse large B-cell lymphoma (DLBCL). LUBAC displays the unique feature to generate so called linear ubiquitin chains. In contrast to any other type of ubiquitin chains, linear or M1-linked ubiquitin chains are formed via a peptide bond between the C-terminal glycine and the N-terminal methionine of two adjacent ubiquitin molecules. It has been shown that the synthesis and attachment of linear ubiquitin chains to key elements of the NF-κB pathway are a prerequisite for its activation. To date LUBAC is the only known enzyme, which can mediate these functions. Currently the ligase complex is extensively investigated to explore its therapeutic potential, in particular for the development as an anti-cancer drug target for patients with DLBCL.