Project presentation 2022

OTUB1-dependent regulation of cell death signaling determines the outcome of Listeria-infection and central nervous system autoimmunity

Josephine Koschel, Gopala Nishanth, Sissy Just, Kunjan Harit, Andrea Kröger, Martina Deckert, Michael Naumann, Dirk Schlüter

The regulation of cell death of infected cells is a critical parameter for the course of infections. Cell death is controlled by different signal transduction pathways. Different external stimuli can induce cell death signaling pathways and, as in the case of tumor necrosis factor (TNF), activate cytoprotective signaling pathways in addition to cell death by apoptosis and necroptosis. The decision to induce TNF-dependent apoptosis, necroptosis or cell death-inhibiting NF-kB signaling is controlled by TNF receptor-associated signal transduction complexes. In these complexes, post-translational modifications by ubiquitination and deubiquitination of individual signal transduction molecules play a crucial role.

In the Research Report 2022, we present a project of the research group of microbiologist Dirk Schlüter, which reveals that the deubiquitinase OTUB1 prevents TNF-induced necroptosis of human and murine hepatocytes during infection with the bacterium Listeria monocytogenes. Mechanistically, OTUB1 reduces K48 polyubiquitination of the cellular inhibitor of apoptosis (c-IAP1) and thereby its degradation. In the absence of OTUB1, proteasomal degradation of c-IAP1 occurs, leading to reduced K63 polyubiquitination and increased phopshorylation of RIP kinase 1 (RIPK1) and the formation of the RIPK1/RIPK3 necrosome with subsequent cell death of hepatocytes. This mechanism of OTUB1-dependent cell death of hepatocytes occurred not only in the murine model of listeriosis, but also after stimulation with TNF, demonstrating the fundamental importance of OTUB1 for the regulation of TNF-dependent necroptosis in hepatocytes.

Induced cell death also plays an important role in autoimmune diseases and recent work from the Schlüter lab shows that OTUB1 prevents CD95-induced cell death of autoimmune CD4+ cells in the CNS in an experimental CD4+ T cell-mediated autoimmune disease of the central nervous system (CNS). This lack of elimination of intracerebral autoimmune CD4+ T cells leads to exacerbation and persistence of the clinical symptoms of the autoimmune disease.

In summary, these studies show that the complex and dynamic interplay of ubiquitination and deubiquitination has fundamental effects on cell death and a decisive influence on the course of infections and autoimmune diseases. further in-depth work is required to exploit the therapeutic potential of these mechanisms of cell death regulation, as these processes are regulated in a cell-type-specific and, in some cases, disease-specific manner.