Ubiquitin-specific protease 25 regulates TLR4-dependent innate immune responses through deubiquitination of the adaptor protein TRAF3.
Ubiquitin-specific protease 25 regulates TLR4-dependent innate immune responses through deubiquitination of the adaptor protein TRAF3.
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DOI：
10.1126/scisignal.2003708
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发表时间：
2013-05-14
影响因子：
7.3
通讯作者：
Dong C
中科院分区：
文献类型：
--
作者：
Zhong B;Liu X;Wang X;Liu X;Li H;Darnay BG;Lin X;Sun SC;Dong C
蛋白质泛素化在Toll样受体(TLR)信号转导和先天免疫中起着重要作用。尽管在TLRs下游发现了几种E3泛素连接酶，但对TLR触发的天然免疫反应中蛋白质去泛素化的调控知之甚少。我们发现泛素特异性蛋白水解酶25(USP25)是TLR信号的调节因子。USP25被招募到TLR4信号复合体中，并与TLR4与其配体脂多糖(LPS)刺激后的接头蛋白肿瘤坏死因子受体相关因子3(TRAF3)和TRAF6相关。USP25特异性地逆转了由E3泛素连接酶cIAP2(细胞凋亡抑制因子2)介导的Lys48连接的TRAF3的泛素化。USP25的缺失增加了TRAF3的泛素化程度，并在TLR4激活后加速了TRAF3的降解，从而增强了TLR4诱导的核因子κB(核因子κB)和丝裂原活化蛋白激酶(MAPK)信号，但抑制了转录因子IRF3(干扰素调节因子3)的激活。与野生型小鼠相比，USP25基因缺陷小鼠对脂多糖诱导的感染性休克的易感性增加，这与促炎细胞因子的产生增加和干扰素-α的产生减少有关。因此，通过抑制TLR4激活过程中TRAF3的降解，USP25能够实现平衡的先天免疫反应。
Protein ubiquitination plays a critical role in Toll-like receptor (TLR) signaling and innate immunity. Although several E3 ubiquitin ligases have been identified downstream of TLRs, the regulation of protein deubiquitination in TLR-triggered innate immune responses is poorly understood. We identified ubiquitin-specific protease 25 (USP25) as a regulator of TLR signaling. USP25 was recruited to the TLR4 signaling complex, and it associated with the adaptor proteins tumor necrosis factor receptor–associated factor 3 (TRAF3) and TRAF6 after stimulation of TLR4 with its ligand lipopolysaccharide (LPS). USP25 specifically reversed the Lys48-linked ubiquitination of TRAF3 that was mediated by the E3 ubiquitin ligase cIAP2 (cellular inhibitor of apoptosis 2). Deficiency in USP25 enhanced the extent of ubiquitination of TRAF3 and accelerated its degradation after TLR4 activation, which potentiated TLR4-induced activation of NF-κB (nuclear factor κB) and MAPK (mitogen-activated protein kinase) signaling, but inhibited activation of the transcription factor IRF3 (interferon regulatory factor 3). USP25-deficient mice exhibited increased susceptibility to LPS-induced septic shock compared to their wild-type counterparts, which was associated with enhanced production of proinflammatory cytokines and decreased production of interferon-α. Thus, by inhibiting the degradation of TRAF3 during TLR4 activation, USP25 enables a balanced innate immune response.
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影响因子：
64.5
作者：
Kagan JC
通讯作者：
Kagan JC
PELI1促进了TRIF依赖性Toll样受体信号传导和促炎性细胞因子的产生。
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
16
作者：
Meulmeester, Erik;Kunze, Marion;Melchior, Frauke
通讯作者：
Melchior, Frauke
DOI：
10.1126/science.1183021
发表时间：
2010-01-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Iwasaki A;Medzhitov R
通讯作者：
Medzhitov R