CRL4(DCAF2) negatively regulates IL-23 production in dendritic cells and limits the development of psoriasis.
CRL4(DCAF2) negatively regulates IL-23 production in dendritic cells and limits the development of psoriasis.
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CRL4(DCAF2) 负向调节树突状细胞中 IL-23 的产生并限制银屑病的发展
DOI：
10.1084/jem.20180210
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发表时间：
2018-08-06
期刊：
影响因子：
--
通讯作者：
Jin J
中科院分区：
文献类型：
--
作者：
Huang T;Gao Z;Zhang Y;Fan K;Wang F;Li Y;Zhong J;Fan HY;Cao Q;Zhou J;Xiao Y;Hu H;Jin J
NF-κB活化失调与免疫紊乱有关。Huang等揭示了CRL 4DCAF 2作为控制DC中NIK稳定性的负调节因子。银屑病患者DCAF 2水平降低与非经典NF-κB活化和IL-23产生增加有关E3连接酶CRL 4DCAF 2被认为是细胞周期的关键调节因子，并且是有丝分裂和S期进展所必需的。NEDD 8靶向药物MLN 4924可灭活cullin环指泛素连接酶（CRL），已在各种类型淋巴瘤和急性髓性白血病的临床试验中进行了检查。然而，CRL 4DCAF 2在原代骨髓细胞中的重要作用仍然知之甚少。MLN 4924处理模拟DCAF 2耗竭，也可促进小鼠银屑病模型的严重程度，这与各种自身免疫性疾病中DCAF 2表达降低的效应一致。使用转录组学和免疫学方法，我们表明，树突状细胞（DC）中的CRL 4 DCAF 2调节NIK的蛋白水解命运，并负调控IL-23的产生。CRL 4DCAF 2促进NIK的多聚泛素化和随后的降解，而不依赖于TRAF 3的降解。DCAF 2缺陷促进NIK积累和RelB核转位。DCAF 2 DC条件性基因敲除小鼠对自身免疫性疾病的敏感性增加。这项研究表明，CRL 4DCAF 2对于控制NIK稳定性至关重要，并强调了控制炎症性疾病的独特机制。
Deregulated NF-κB activation is linked to immunological disorders. Huang et al. revealed CRL4DCAF2 as a negative regulator in controlling NIK stability in DCs. Lower level of DCAF2 is associated with noncanonical NF-κB activation and hyperproduction of IL-23 in psoriasis patients. The E3 ligase CRL4DCAF2 is believed to be a pivotal regulator of the cell cycle and is required for mitotic and S phase progression. The NEDD8-targeting drug MLN4924, which inactivates cullin ring-finger ubiquitin ligases (CRLs), has been examined in clinical trials for various types of lymphoma and acute myeloid leukemia. However, the essential role of CRL4DCAF2 in primary myeloid cells remains poorly understood. MLN4924 treatment, which mimics DCAF2 depletion, also promotes the severity of mouse psoriasis models, consistent with the effects of reduced DCAF2 expression in various autoimmune diseases. Using transcriptomic and immunological approaches, we showed that CRL4DCAF2 in dendritic cells (DCs) regulates the proteolytic fate of NIK and negatively regulates IL-23 production. CRL4DCAF2 promoted the polyubiquitination and subsequent degradation of NIK independent of TRAF3 degradation. DCAF2 deficiency facilitated NIK accumulation and RelB nuclear translocation. DCAF2 DC-conditional knockout mice displayed increased sensitivity to autoimmune diseases. This study shows that CRL4DCAF2 is crucial for controlling NIK stability and highlights a unique mechanism that controls inflammatory diseases.
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影响因子：
30.5
作者：
通讯作者：
--
DOI：
10.1007/978-1-4939-2926-9_15
发表时间：
2016-01-01
期刊：
CYCLIN-DEPENDENT KINASE (CDK) INHIBITORS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Hoodless, Laura J.;Robb, Calum T.;Rossi, Adriano G.
通讯作者：
Rossi, Adriano G.
影响因子：
11.4
作者：
Chow, EK;O'Connell, RM;Cheng, GH
通讯作者：
Cheng, GH
影响因子：
50.3
作者：
Kortylewski M;Xin H;Kujawski M;Lee H;Liu Y;Harris T;Drake C;Pardoll D;Yu H
通讯作者：
Yu H
在终末分化的中性粒细胞中，源源凋亡与炎症相关的细胞周期无关。
影响因子：
15.3
作者：
Altznauer, F;Martinelli, S;Yousefi, S;Thürig, C;Schmid, I;Conway, EM;Schöni, MH;Vogt, P;Mueller, C;Fey, MF;Zangemeister-Wittke, U;Simon, HU
通讯作者：
Simon, HU