Astrocyte-specific function of OTUB1 in experimental autoimmune encephalomyelitis

• Applicant: Xu Wang, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Immunology
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 302097871

Astrocytes play an important immunoregulatory role in experimental autoimmune encephalomyelitis (EAE), an animal model for the human autoimmune disease multiple sclerosis. Previously, we have shown that astrocyte-specific Fas ligand contributes to EAE recovery by inducing apoptosis of infiltrating encephalitogenic T cells. Additionally, we identified that A20, a deubiquitinase (DUB), inhibits NF-kB and STAT1 activation in astrocytes, which ameliorates EAE. Recently, another DUB, OTU deubiquitinase, ubiquitin aldehyde binding 1 (OTUB1) has been shown to be important for the regulation of NF-kB and apoptosis. However, the in vivo function of OTUB1 is largely unknown. To address the astrocyte-specific function of OTUB1, we generated mice lacking OTUB1 selectively in astrocytes. These GFAP-Cre OTUB1fl/fl mice developed a significantly more severe EAE with increased infiltration of T cells, dendritic cells and macrophages in the spinal cord as compared to control mice. Compared to control cells, OTUB1-deficient astrocytes produced significantly higher levels of CXCL10, CXCL11, and NOS2 upon stimulation with IFN-gamma in vitro. Based on these results, we aim to further elucidate the astrocyte-specific regulatory mechanisms and molecular function of OTUB1 in EAE in the applied project.

• DFG Programme: Research Grants