USP11 negatively regulates TNFalpha-induced NF-kappaB activation by targeting on IkappaBalpha.
USP11 negatively regulates TNFalpha-induced NF-kappaB activation by targeting on IkappaBalpha.
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DOI：
10.1016/j.cellsig.2009.10.008
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发表时间：
2010-03
影响因子：
4.8
通讯作者：
Yang J
中科院分区：
文献类型：
--
作者：
Sun W;Tan X;Shi Y;Xu G;Mao R;Gu X;Fan Y;Yu Y;Burlingame S;Zhang H;Rednam SP;Lu X;Zhang T;Fu S;Cao G;Qin J;Yang J
I-κBα是核因子-κB转录因子在细胞质中固存的中心锚定分子。泛素化介导的IκBα降解紧随其后，是核转录因子κB核转位和激活所必需的。然而，IκBα去泛素化的确切机制仍不完全清楚。利用蛋白质组学方法，我们鉴定了泛素特异肽酶11(USP11)是一种与IκBα相关的脱泛素酶。USP11过表达抑制IκBα泛素化。重组USP11体外催化I-κ-B-α脱泛素化此外，下调USP11的表达可增强肿瘤坏死因子α诱导的IκBα泛素化和核因子κB的激活。这些数据表明，USP11在下调肿瘤坏死因子α介导的NF-κB激活中起重要作用，它通过调节IκBα的稳定性而发挥作用。此外，过度表达催化失活的USP11突变体部分地抑制了肿瘤坏死因子α和IKKβ诱导的NF-κB的激活，这表明USP11在负调控肿瘤坏死因子α介导的NF-κB激活方面也发挥了非催化作用。因此，IκBα泛素化和去泛素化过程在肿瘤坏死因子α诱导的NF-κB激活中起阴阳调节作用。
IκBα serves as a central anchoring molecule in the sequestration of NF-κB transcription factor in the cytoplasm. Ubiquitination-mediated IκBα degradation immediately precedes and is required for NF-κB nuclear translocation and activation. However, the precise mechanism for the deubiquitination of IκBα is still not fully understood. Using a proteomic approach, we have identified Ubiquitin Specific Peptidase 11 (USP11) as an IκBα associated deubiquitinase. Overexpression of USP11 inhibits IκBα ubiquitination. Recombinant USP11 catalyzes deubiquitination of IκBα in vitro. Moreover, knockdown of USP11 expression enhances TNFα-induced IκBα ubiquitination and NF-κB activation. These data demonstrate that USP11 plays an important role in the downregulation of TNFα-mediated NF-κB activation through modulating IκBα stability. In addition, overexpression of a catalytically inactive USP11 mutant partially inhibits TNFα- and IKKβ-induced NF-κB activation, suggesting that USP11 also exerts a non-catalytic function in its negative regulation of TNFα-mediated NF-κB activation. Thus, IκBα ubiquitination and deubiquitination processes function as a Yin-Yang regulatory mechanism on TNFα-induced NF-κB activation.
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影响因子：
5.3
作者：
SHIMIZU, H;MITOMO, K;YAMAMOTO, K
通讯作者：
YAMAMOTO, K
影响因子：
64.5
作者：
Zandi, E;Rothwarf, DM;Karin, M
通讯作者：
Karin, M
影响因子：
32.4
作者：
Tanaka, M;Fuentes, ME;Goeddel, DV
通讯作者：
Goeddel, DV
影响因子：
4.8
作者：
Mu, Jung-Jung;Wang, Yi;Qin, Jun
通讯作者：
Qin, Jun
DOI：
10.1126/stke.1999.5.re1
发表时间：
1999-10-26
期刊：
Science's STKE : signal transduction knowledge environment
影响因子：
--
作者：
Rothwarf, D M;Karin, M
通讯作者：
Karin, M