Immunregulatory function of the deubiquitinylating enzymes A20 and OTUB1 in infectious and autoimmune diseases

We focus on NF-κB-dependent immune response and their regulation by the DUBs A20 and otubain-1 (OTUB1). With respect to A20, we concentrate on its role in T cells, because our preliminary work shows that T cell-specific deletion of A20 has a protective effect in listeriosis and reduces the clinical severity of EAE (Experimental Autoimmune Encephalomyelitis). We hypothesize that loss of A20 augments the expansion of pathogen-specific T cells, thus, resulting in improved control of L. monocytogenes. Moreover, its loss may lead to increased numbers of regulatory T cells in EAE. Thus, we characterize the molecular function of A20 in these disorders. In addition, we have established a novel conditional OTUB1-deficient mouse strain. OTUB1 has a preferential specificity for K48-linked ubiquitin chains but can also inhibit ubiquitin transfer from E2 to E3 ligases and, thus, block ubiquitination of E3 ligase target molecules. The in vivo function of OTUB1 is unknown and OTUB1-deficient mice have not been reported so far. First results from our novel conditional OTUB1-deficient mouse strain show that ubiquitous OTUB1 deletion results in embryonic lethality. However, mice with either DC- or T cell-specific OTUB1-deletion are viable, and we use these mouse strains to study the function of OTUB1 in DCs and T cells in listeriosis, toxoplasmosis and EAE. To gain mechanistic insights in the cellular function of OTUB1 we analyze its modifications and intricate interactions with target molecules during infection. The comparison of mice with DC and T cell-specific deletion of A20 and OTUB1, respectively, will help to understand the differential regulation of immune responses by these two NF-κB-regulating DUBs.