Plasticity and cell-type specific functions of OTUB1 in infection

Deubiquitinating enzymes (DUBs) are critical regulators of immune responses and A05 aims to decipher cellular and molecular functions of the DUBs CYLD, A20 and OTUB1 in infectious and autoimmune disorders. Within the 1^st funding period, A05 defined that CYLD impairs protective immune responses in listeriosis by inhibiting STAT3-dependent fibrin production in hepatocytes. The 2^nd period originated, that CYLD (1) deubiquitinates RIPK2 and inhibits NOD2/RIPK2-mediated autophagy, ROS and NO production in macrophages, and (2) suppresses NF- B-dependent activation in DCs. In contrast, B cell-expressed A20 is essential to prevent spontaneous autoimmunity, whereas DC-specific A20 is required to prevent lethality upon low-dose LPS challenge. In support of a cell type-specific function of DUBs, A05 illustrated that A20 diminishes primary CD8⁺ T cell responses in listeriosis but augments secondary CD8⁺ T cell responses by preventing CD95- and TNF-mediated apoptosis and necroptosis of pathogen-specific memory T cells. Importantly, A05 has established a novel conditional OTUB1 mouse strain and has identified that OTUB1 regulates (1) JAK-dependent cytokine receptor signaling in T cells and (2) TLR/MyD88 -mediated NF- B activation in DCs. In T cells, A05 identified that OTUB1 interacts with and stabilizes SOCS1, which suppresses JAK/STAT signaling. In DCs, OTUB1 is required for Toxoplasma-induced TLR11/12-MyD88-dependent NF- B activation and protective IL-12 production. In the 3^rd funding period, A05 will finalize its work on T cell-specific OTUB1 in EAE and DC-specific OTUB1 in toxoplasmosis. In collaboration with other projects of CRC854, A05 will extend its studies to the role of OTUB1 in (1) T cells, (2) DCs, (3) macrophages/granulocytes and (4) hepatocytes in the murine model of listeriosis. Preliminary data already show that the plasticity of the function of OTUB1 is determined by the underlying disease and additionally support our concept of a cell type-specific function OTUB. In fact in listeriosis, OTUB1 (1) prevents cell death of hepatocytes, (2) inhibits cytokine production of DC and (3) is required for T-cell- and macrophage-dependent pathogen control. Therefore, the focus of the studies will be to determine the molecular mechanisms of the cell type-specific function and plasticity of OTUB1, i.e. in listeriosis.