The deubiquitinase OTUB1 augments NF-κB-dependent immune responses in dendritic cells in infection and inflammation by stabilizing UBC13.
The deubiquitinase OTUB1 augments NF-κB-dependent immune responses in dendritic cells in infection and inflammation by stabilizing UBC13.
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DOI：
10.1038/s41423-020-0362-6
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发表时间：
2021-06
影响因子：
24.1
通讯作者：
Schlüter D
中科院分区：
文献类型：
--
作者：
Mulas F;Wang X;Song S;Nishanth G;Yi W;Brunn A;Larsen PK;Isermann B;Kalinke U;Barragan A;Naumann M;Deckert M;Schlüter D
树突状细胞(DC)对于抵御病原体是不可或缺的，但也可能对免疫病理起到作用。Toll样受体(Toll-like Receptor，TLR)对病原体的激活主要由模式识别受体/核因子-κB(NF-κB)信号介导，依赖于相应信号分子的适当泛素化。然而，涉及的泛素化和去泛素化的酶以及它们之间的相互作用还不完全清楚。在这里，我们揭示了脱泛素酶OTU结构域，泛素醛结合1(OTUB1)在小鼠弓形虫感染和脂多糖攻击下在DC中上调。TLR2、TLR3、TLR7和TLR9特异性刺激DCs后，TLR11/12TLR11/12配体和TLR4配体脂多糖刺激树突状细胞可诱导κB活化，导致IL-6、IL-12和肿瘤坏死因子的产生增加。机制上，OTUB1通过K48连接的去泛素化和E2结合酶UBC13的稳定，促进树突状细胞中NF-κB的活性，导致K63连接的IRAK1(IL-1受体相关激酶1)和TRAF6(肿瘤坏死因子相关因子6)的泛素化增加。因此，DC特异性的OTUB1基因的缺失削弱了DC在感染弓形虫的头两天内产生的细胞因子，特别是IL-12，导致自然杀伤细胞产生保护性干扰素-γ(干扰素-γ)的减少，削弱了对寄生虫复制的控制，最终导致慢性脑炎死亡，所有这些都可以通过在感染的前3天进行低剂量的IL-12治疗来预防。相反，OTUB1缺陷树突状细胞激活和细胞因子产生受损，可保护小鼠免受内毒素诱导的免疫病理影响。总而言之，这些发现确认OTUB1是感染和炎症性疾病期间DC的一种有效的新调节因子。
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-κB (NF-κB) 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-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 TLR9. Mechanistically, 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 T. gondii 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 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.
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影响因子：
6.7
作者：
Chan B;Gonçalves Magalhães V;Lemmermann NAW;Juranić Lisnić V;Stempel M;Bussey KA;Reimer E;Podlech J;Lienenklaus S;Reddehase MJ;Jonjić S;Brinkmann MM
通讯作者：
Brinkmann MM
具有未验证抗体的蛋白质印迹不准确：需要蛋白质印迹最小的报告标准（WBMR）。
影响因子：
3.7
作者：
Gilda JE;Ghosh R;Cheah JX;West TM;Bodine SC;Gomes AV
通讯作者：
Gomes AV
DOI：
10.1084/jem.20062648
发表时间：
2007-07-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Caton ML;Smith-Raska MR;Reizis B
通讯作者：
Reizis B
影响因子：
30.5
作者：
Choi, Kyung-Chul;Lee, Youn Sook;Park, Seok Hee
通讯作者：
Park, Seok Hee
影响因子：
4.1
作者：
Edelmann, Mariola J.;Iphofer, Alexander;Kessler, Benedikt M.
通讯作者：
Kessler, Benedikt M.