Targeting F box protein Fbxo3 to control cytokine-driven inflammation.
Targeting F box protein Fbxo3 to control cytokine-driven inflammation.
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DOI：
10.4049/jimmunol.1300456
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发表时间：
2013-11-15
期刊：
影响因子：
--
通讯作者：
Chen BB
中科院分区：
文献类型：
--
作者：
Mallampalli RK;Coon TA;Glasser JR;Wang C;Dunn SR;Weathington NM;Zhao J;Zou C;Zhao Y;Chen BB
细胞因子驱动的炎症是一系列感染性和免疫相关疾病的病理生物学基础。肿瘤坏死因子受体相关因子(TRAF)蛋白通过传递细胞表面受体的信号来诱导编码致炎细胞因子的基因的转录激活，在先天免疫中发挥重要作用。我们发现，泛素E3连接酶F盒组分，称为Fbxo3，通过介导TRAF抑制蛋白Fbxl2的降解，有效地刺激人炎症细胞分泌细胞因子。对Fbxo3羧基末端结构的分析表明，细菌样APAG的分子特征对于介导Fbxl2的释放和刺激细胞因子的分泌是必不可少的。通过针对这个apag基序，我们开发了一种高度独特的、选择性的小分子Fbxo3抑制剂，它通过降低TRAF蛋白水平，有效地抑制人血单个核细胞释放细胞因子。Fbxo3抑制剂有效地减轻了小鼠模型中病毒性肺炎、感染性休克、结肠炎和细胞因子驱动的炎症的严重程度。因此，Fbxo3的药理靶向可能是治疗以增强宿主炎症反应为特征的免疫相关疾病的一种有前途的策略。
Cytokine-driven inflammation underlies the pathobiology of a wide array of infectious and immune-related disorders. The tumor necrosis factor receptor-associated factor (TRAF) proteins have a vital role in innate immunity by conveying signals from cell surface receptors to elicit transcriptional activation of genes encoding pro-inflammatory cytokines. We discovered that a ubiquitin E3 ligase F box component, termed Fbxo3, potently stimulates cytokine secretion from human inflammatory cells by mediating the degradation of the TRAF inhibitory protein, Fbxl2. Analysis of the Fbxo3 carboxyl-terminal structure revealed that the bacterial-like ApaG molecular signature was indispensible for mediating Fbxl2 disposal and stimulating cytokine secretion. By targeting this ApaG motif, we developed a highly unique, selective genus of small molecule Fbxo3 inhibitors that by reducing TRAF protein levels, potently inhibited cytokine release from human blood mononuclear cells. The Fbxo3 inhibitors effectively lessened the severity of viral pneumonia, septic shock, colitis, and cytokine-driven inflammation systemically in murine models. Thus, pharmacological targeting of Fbxo3 might be a promising strategy for immune-related disorders characterized by a heightened host inflammatory response.
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影响因子：
17.1
作者：
London NR;Zhu W;Bozza FA;Smith MC;Greif DM;Sorensen LK;Chen L;Kaminoh Y;Chan AC;Passi SF;Day CW;Barnard DL;Zimmerman GA;Krasnow MA;Li DY
通讯作者：
Li DY
影响因子：
5.1
作者：
Bralley, Eve E.;Greenspan, Phillip;Hartle, Diane K.
通讯作者：
Hartle, Diane K.
影响因子：
5.3
作者：
Chen, Bill B.;Coon, Tiffany A.;Mallampalli, Rama K.
通讯作者：
Mallampalli, Rama K.
DOI：
10.1107/s1744309105018956
发表时间：
2005-07-01
影响因子：
0.9
作者：
Chin, KH;Chou, CC;Chou, SH
通讯作者：
Chou, SH
影响因子：
4.8
作者：
Liu, L;Rodriguez-Bèlmonte, EM;Lee, MYWT
通讯作者：
Lee, MYWT