Dendritic cell-specific function of OTUB1 in inflammation and infection

Abstract

Dendritic cells (DCs) are key sentinel and professional antigen-presenting cells (APCs) of the immune system. They bridge the innate and adaptive immune responses, and play indispensable roles in the host defence against invading pathogens including viruses, bacteria, and parasites, but may also contribute to immunopathology. Activation of DCs upon sensing of pathogens by Toll-like receptors (TLRs) is largely mediated by NF-κB signaling, which broadly depends on the appropriate ubiquitination of the respective signaling molecules. However, the involved ubiquitinating and deubiquitinating enzymes and their interaction are only incompletely understood. Here, we identified that the deubiquitinase OTU domain, ubiquitin aldehyde binding 1 (OTUB1) is upregulated in vivo and in vitro in DCs upon murine Toxoplasma (T.) gondii infection and lipopolysaccharide (LPS) challenge. Stimulation of DCs with the TLR11/12 ligand T. gondii profilin and the TLR4 ligand LPS induced an increased NF-κB activation in OTUB1-competent cells resulting in elevated IL-6, IL-12 and TNF production, which was also observed upon specific stimulation of TLR2, TLR3, TLR7, and TLR9. Mechanistically, OTUB1 promoted NF-κB activity in DCs by removing K48 ubiquitination and, therefore, by stabilizing the E2 conjugating enzyme UBC13 resulting in increased K63 ubiquitination of IRAK1 and TRAF6. Consequently, DC-specific deletion of OTUB1 impaired cytokine production, in particular IL-12, of DCs in the first two days of T. gondii infection resulting in diminished production of protective IFN-γ by NK cells, an impaired control of parasite replication and, finally, death from chronic Toxoplasma encephalitis, which all could be prevented by low-dose IL-12 treatment in the first three days of infection. In contrast, impaired activation and cytokine production of OTUB1-deficient DCs protected mice from LPS-induced immunopathology. Collectively, these experiments identified OTUB1 as a potent novel regulator of DCs during infectious and inflammatory diseases.