PMID- 32024978 OWN - NLM STAT- MEDLINE DCOM- 20220126 LR - 20240226 IS - 2042-0226 (Electronic) IS - 1672-7681 (Print) IS - 1672-7681 (Linking) VI - 18 IP - 6 DP - 2021 Jun TI - The deubiquitinase OTUB1 augments NF-kappaB-dependent immune responses in dendritic cells in infection and inflammation by stabilizing UBC13. PG - 1512-1527 LID - 10.1038/s41423-020-0362-6 [doi] AB - Dendritic cells (DCs) are indispensable for defense against pathogens but may also contribute to immunopathology. Activation of DCs upon the sensing of pathogens by Toll-like receptors (TLRs) is largely mediated by pattern recognition receptor/nuclear factor-kappaB (NF-kappaB) signaling and depends on the appropriate ubiquitination of the respective signaling molecules. However, the ubiquitinating and deubiquitinating enzymes involved and their interactions are only incompletely understood. Here, we reveal that the deubiquitinase OTU domain, ubiquitin aldehyde binding 1 (OTUB1) is upregulated in DCs upon murine Toxoplasma gondii infection and lipopolysaccharide challenge. Stimulation of DCs with the TLR11/12 ligand T. gondii profilin and the TLR4 ligand lipopolysaccharide induced an increase in NF-kappaB activation in OTUB1-competent cells, resulting in elevated interleukin-6 (IL-6), IL-12, and tumor necrosis factor (TNF) production, which was also observed upon the specific stimulation of TLR2, TLR3, TLR7, and TLR9. Mechanistically, OTUB1 promoted NF-kappaB activity in DCs by K48-linked deubiquitination and stabilization of the E2-conjugating enzyme UBC13, resulting in increased K63-linked ubiquitination of IRAK1 (IL-1 receptor-associated kinase 1) and TRAF6 (TNF receptor-associated factor 6). Consequently, DC-specific deletion of OTUB1 impaired the production of cytokines, in particular IL-12, by DCs over the first 2 days of T. gondii infection, resulting in the diminished production of protective interferon-gamma (IFN-gamma) by natural killer cells, impaired control of parasite replication, and, finally, death from chronic T. encephalitis, all of which could be prevented by low-dose IL-12 treatment in the first 3 days of infection. In contrast, impaired OTUB1-deficient DC activation and cytokine production by OTUB1-deficient DCs protected mice from lipopolysaccharide-induced immunopathology. Collectively, these findings identify OTUB1 as a potent novel regulator of DCs during infectious and inflammatory diseases. FAU - Mulas, Floriana AU - Mulas F AD - Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, 39120, Magdeburg, Germany. AD - Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625, Hannover, Germany. FAU - Wang, Xu AU - Wang X AUID- ORCID: 0000-0001-8428-9339 AD - Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, 39120, Magdeburg, Germany. sunrim@163.com. AD - Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625, Hannover, Germany. sunrim@163.com. AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China. sunrim@163.com. FAU - Song, Shanshan AU - Song S AD - Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, 39120, Magdeburg, Germany. FAU - Nishanth, Gopala AU - Nishanth G AD - Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, 39120, Magdeburg, Germany. AD - Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625, Hannover, Germany. FAU - Yi, Wenjing AU - Yi W AD - Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, 39120, Magdeburg, Germany. AD - Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625, Hannover, Germany. FAU - Brunn, Anna AU - Brunn A AD - Department of Neuropathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany. FAU - Larsen, Pia-Katharina AU - Larsen PK AD - Institute for Experimental Infection Research, TWINCORE Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, 30625, Hannover, Germany. FAU - Isermann, Berend AU - Isermann B AD - Institute for Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke University Magdeburg, 39120, Magdeburg, Germany. FAU - Kalinke, Ulrich AU - Kalinke U AUID- ORCID: 0000-0003-0503-9564 AD - Institute for Experimental Infection Research, TWINCORE Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, 30625, Hannover, Germany. AD - Cluster of Excellence-Resolving Infection Susceptibility (RESIST), Hannover Medical School, 30625, Hannover, Germany. FAU - Barragan, Antonio AU - Barragan A AD - Department of Molecular Biosciences, Stockholm University, 10691, Stockholm, Sweden. FAU - Naumann, Michael AU - Naumann M AD - Institute for Experimental Internal Medicine, Otto-von-Guericke University Magdeburg, 39120, Magdeburg, Germany. FAU - Deckert, Martina AU - Deckert M AD - Department of Neuropathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany. FAU - Schluter, Dirk AU - Schluter D AD - Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, 39120, Magdeburg, Germany. schlueter.dirk@mh-hannover.de. AD - Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625, Hannover, Germany. schlueter.dirk@mh-hannover.de. AD - Cluster of Excellence-Resolving Infection Susceptibility (RESIST), Hannover Medical School, 30625, Hannover, Germany. schlueter.dirk@mh-hannover.de. LA - eng GR - SFB 854, TP5/Deutsche Forschungsgemeinschaft (German Research Foundation)/ GR - SFB900-B2/Deutsche Forschungsgemeinschaft (German Research Foundation)/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200205 PL - China TA - Cell Mol Immunol JT - Cellular & molecular immunology JID - 101242872 RN - 0 (CD11 Antigens) RN - 0 (Lipopolysaccharides) RN - 0 (NF-kappa B) RN - 120904-94-1 (Polyubiquitin) RN - 187348-17-0 (Interleukin-12) RN - 82115-62-6 (Interferon-gamma) RN - EC 2.3.2.23 (Ube2n protein, mouse) RN - EC 2.3.2.23 (Ubiquitin-Conjugating Enzymes) RN - EC 3.4.22.- (Cysteine Endopeptidases) RN - EC 3.4.22.- (Otub1 protein, mouse) RN - K3Z4F929H6 (Lysine) SB - IM MH - Animals MH - CD11 Antigens/metabolism MH - Cysteine Endopeptidases/*metabolism MH - Dendritic Cells/*immunology/parasitology MH - Gene Deletion MH - *Immunity MH - Inflammation/*immunology MH - Interferon-gamma/metabolism MH - Interleukin-12/pharmacology MH - Lipopolysaccharides MH - Lysine/metabolism MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - NF-kappa B/*metabolism MH - Polyubiquitin/metabolism MH - Protein Stability MH - Sepsis/immunology/pathology MH - Toxoplasma/physiology MH - Toxoplasmosis/immunology/pathology MH - Ubiquitin-Conjugating Enzymes/*metabolism MH - Ubiquitination MH - Up-Regulation MH - Mice PMC - PMC8167118 OTO - NOTNLM OT - OTUB1 OT - dendritic cell OT - innate immunity OT - signal transduction OT - ubiquitination COIS- The authors declare no competing interests. EDAT- 2020/02/07 06:00 MHDA- 2022/01/27 06:00 PMCR- 2020/02/05 CRDT- 2020/02/07 06:00 PHST- 2019/07/29 00:00 [received] PHST- 2020/01/01 00:00 [accepted] PHST- 2020/02/07 06:00 [pubmed] PHST- 2022/01/27 06:00 [medline] PHST- 2020/02/07 06:00 [entrez] PHST- 2020/02/05 00:00 [pmc-release] AID - 10.1038/s41423-020-0362-6 [pii] AID - 362 [pii] AID - 10.1038/s41423-020-0362-6 [doi] PST - ppublish SO - Cell Mol Immunol. 2021 Jun;18(6):1512-1527. doi: 10.1038/s41423-020-0362-6. Epub 2020 Feb 5.