USP18 inhibits NF-κB and NFAT activation during Th17 differentiation by deubiquitinating the TAK1-TAB1 complex.
USP18 inhibits NF-κB and NFAT activation during Th17 differentiation by deubiquitinating the TAK1-TAB1 complex.
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DOI：
10.1084/jem.20122327
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发表时间：
2013-07-29
期刊：
影响因子：
--
通讯作者：
Dong C
中科院分区：
文献类型：
--
作者：
Liu X;Li H;Zhong B;Blonska M;Gorjestani S;Yan M;Tian Q;Zhang DE;Lin X;Dong C
泛素特异性蛋白酶18抑制TAK 1-TAB复合物的泛素化以限制IL-2产生并促进Th 17分化和自身免疫应答。细胞信号分子的可逆泛素修饰已经成为细胞响应细胞外刺激的关键机制。尽管TGF-β激活激酶1（TAK 1）的泛素化对于T细胞中NF-κB的活化至关重要，但其去泛素化的调控机制尚不清楚。我们表明，USP 18，这是以前报道的是重要的调节I型干扰素信号在先天免疫，调节T细胞活化和辅助性T细胞17（Th 17）细胞分化的去泛素化的TAK 1-TAB 1复合物。USP 18缺陷型T细胞在Th 17分化方面存在缺陷，而Usp 18 −/−小鼠对实验性自身免疫性脑脊髓炎（EAE）具有抗性。与野生型对照相比，USP 18缺陷型T细胞对T细胞受体结合的反应是NF-κB和NFAT的过度活化，并产生增加水平的IL-2。重要的是，USP 18与TAK 1-TAB 1复合物相关并使其去泛素化，从而限制IL-2的表达。因此，我们的研究结果表明，在Th 17分化过程中，TAK 1活性存在以前未表征的负调控，这表明USP 18可能被靶向治疗自身免疫性疾病。
Ubiquitin-specific protease 18 inhibits ubiquitination of TAK1–TAB complexes to restrict IL-2 production and promote Th17 differentiation and autoimmune responses. Reversible ubiquitin modification of cell signaling molecules has emerged as a critical mechanism by which cells respond to extracellular stimuli. Although ubiquitination of TGF-β–activated kinase 1 (TAK1) is critical for NF-κB activation in T cells, the regulation of its deubiquitination is unclear. We show that USP18, which was previously reported to be important in regulating type I interferon signaling in innate immunity, regulates T cell activation and T helper 17 (Th17) cell differentiation by deubiquitinating the TAK1–TAB1 complex. USP18-deficient T cells are defective in Th17 differentiation and Usp18−/− mice are resistant to experimental autoimmune encephalomyelitis (EAE). In response to T cell receptor engagement, USP18-deficient T cells exhibit hyperactivation of NF-κB and NFAT and produce increased levels of IL-2 compared with the wild-type controls. Importantly, USP18 is associated with and deubiquitinates the TAK1–TAB1 complex, thereby restricting expression of IL-2. Our findings thus demonstrate a previously uncharacterized negative regulation of TAK1 activity during Th17 differentiation, suggesting that USP18 may be targeted to treat autoimmune diseases.
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作者：
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10.1073/pnas.1110946108
发表时间：
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影响因子：
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影响因子：
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