The deubiquitinase OTUB1 augments NF-κB-dependent immune responses in dendritic cells in infection and inflammation by stabilizing UBC13

作     者：Floriana Mulas Xu Wang Shanshan Song Gopala Nishanth Wenjing Yi Anna Brunn Pia-Katharina Larsen Berend Isermann Ulrich Kalinke Antonio Barragan Michael Naumann Martina Deckert Dirk Schlüter Floriana Mulas;Xu Wang;Shanshan Song;Gopala Nishanth;Wenjing Yi;Anna Brunn;Pia-Katharina Larsen;Berend Isermann;Ulrich Kalinke;Antonio Barragan;Michael Naumann;Martina Deckert;Dirk Schlüter

作者机构：Institute of Medical Microbiology and Hospital HygieneOtto-von-Guericke University Magdeburg39120MagdeburgGermany Institute of Medical Microbiology and Hospital EpidemiologyHannover Medical School30625HannoverGermany Chemical Biology Research CenterSchool of Pharmaceutical SciencesWenzhou Medical University325035WenzhouChina Department of NeuropathologyFaculty of Medicine and University Hospital CologneUniversity of Cologne50931CologneGermany Institute for Experimental Infection ResearchTWINCORE Centre for Experimental and Clinical Infection Researcha joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research30625HannoverGermany Institute for Clinical Chemistry and PathobiochemistryOtto-von-Guericke University Magdeburg39120MagdeburgGermany Cluster of Excellence-Resolving Infection Susceptibility(RESIST)Hannover Medical School30625HannoverGermany Department of Molecular BiosciencesStockholm University10691StockholmSweden Institute for Experimental Internal MedicineOtto-von-Guericke University Magdeburg39120MagdeburgGermany 

出 版 物：《Cellular & Molecular Immunology》 (中国免疫学杂志（英文版）)

年 卷 期：2021年第18卷第6期

页      面：1512-1527页

核心收录：

学科分类：1001[医学-基础医学(可授医学、理学学位)] 100102[医学-免疫学] 10[医学] 

基　　金：funded by the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)-Project-ID 97850925-SFB 854(project TP5 to M.N.and DS),Project-ID 406922110-Joint French-German Project cGASVAC(to U.K.) Project-ID 158989968-SFB900(project B2 to U.K.) 

主　　题：OTUB1 dendritic cell signal transduction ubiquitination innate immunity 

摘      要：Dendritic cells(DCs)are indispensable for defense against pathogens but may also contribute to *** of DCs upon the sensing of pathogens by Toll-like receptors(TLRs)is largely mediated by pattern recognition receptor/nuclear factor-κB(NF-κB)signaling and depends on the appropriate ubiquitination of the respective signaling ***,the ubiquitinating and deubiquitinating enzymes involved and their interactions are only incompletely ***,we reveal that the deubiquitinase OTU domain,ubiquitin aldehyde binding 1(OTUB1)is upregulated in DCs upon murine Toxoplasma gondii infection and lipopolysaccharide *** of DCs with the TLR11/12 ligand *** profilin and the TLR4 ligand lipopolysaccharide induced an increase in NF-κB 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 ***,OTUB1 promoted NF-κB 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 *** infection,resulting in the diminished production of protective interferon-γ(IFN-γ)by natural killer cells,impaired control of parasite replication,and,finally,death from chronic ***,all of which could be prevented by low-dose IL-12 treatment in the first 3 days of *** contrast,impaired OTUB1-deficient DC activation and cytokine production by OTUB1-deficient DCs protected mice from lipopolysaccharide-induced ***,these findings identify OTUB1 as a potent novel regulator of DCs during infectious and inflammatory diseases.