Ubiquitin-associated Domain-containing Ubiquitin Regulatory X (UBX) Protein UBXN1 Is a Negative Regulator of Nuclear Factor κB (NF-κB) Signaling
Ubiquitin-associated Domain-containing Ubiquitin Regulatory X (UBX) Protein UBXN1 Is a Negative Regulator of Nuclear Factor κB (NF-κB) Signaling
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含有泛素相关结构域的泛素调节 X (UBX) 蛋白 UBXN1 是核因子 kappa B (NF-kappa B) 信号传导的负调节因子
DOI：
10.1074/jbc.m114.631689
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发表时间：
2015-04-17
影响因子：
4.8
通讯作者：
Li, Hui-Yan
中科院分区：
文献类型：
--
作者：
Wang, Yu-Bo;Tan, Bo;Li, Hui-Yan
过度的核因子B（NF-B）激活应被精确控制，因为它有助于多种免疫和炎症疾病。然而，NF-B激活的负调控机制仍需阐明。已证明各种类型的聚遍在蛋白链参与NF-B激活过程。许多与泛素化相关的负调节因子，如A20和CYLD，抑制NF-B信号通路中的IB激酶活化。为了发现与泛素化相关的新的NF-B信号调节因子，我们使用了针对51个含有泛素相关结构域的蛋白的小规模siRNA文库，并筛选出UBXN 1，其含有泛素相关和泛素调节X（UBX）结构域作为TNF触发的NF-B活化的负调节因子。UBXN 1的过表达抑制TNF触发的NF-B激活，尽管UBXN 1的敲低具有相反的效果。含有UBX结构域的蛋白质通常作为含有valosin的蛋白质（VCP）/p97辅因子。然而，VCP/p97的敲低几乎不影响UBXN 1介导的NF-B抑制。同时，我们发现UBXN 1与TNF受体复合物中的细胞凋亡抑制蛋白（cIAP）、RIP 1的E3泛素连接酶相互作用。UBXN 1竞争性结合cIAP 1，阻断cIAP 1向TNFR 1的募集，并随后抑制响应TNF的RIP 1多聚泛素化。因此，我们的研究结果表明，UBXN 1是一个重要的负调节TNF触发的NF-B信号通路介导的cIAP募集独立于VCP/p97。
Excessive nuclear factor B (NF-B) activation should be precisely controlled as it contributes to multiple immune and inflammatory diseases. However, the negative regulatory mechanisms of NF-B activation still need to be elucidated. Various types of polyubiquitin chains have proved to be involved in the process of NF-B activation. Many negative regulators linked to ubiquitination, such as A20 and CYLD, inhibit IB kinase activation in the NF-B signaling pathway. To find new NF-B signaling regulators linked to ubiquitination, we used a small scale siRNA library against 51 ubiquitin-associated domain-containing proteins and screened out UBXN1, which contained both ubiquitin-associated and ubiquitin regulatory X (UBX) domains as a negative regulator of TNF-triggered NF-B activation. Overexpression of UBXN1 inhibited TNF-triggered NF-B activation, although knockdown of UBXN1 had the opposite effect. UBX domain-containing proteins usually act as valosin-containing protein (VCP)/p97 cofactors. However, knockdown of VCP/p97 barely affected UBXN1-mediated NF-B inhibition. At the same time, we found that UBXN1 interacted with cellular inhibitors of apoptosis proteins (cIAPs), E3 ubiquitin ligases of RIP1 in the TNF receptor complex. UBXN1 competitively bound to cIAP1, blocked cIAP1 recruitment to TNFR1, and sequentially inhibited RIP1 polyubiquitination in response to TNF. Therefore, our findings demonstrate that UBXN1 is an important negative regulator of the TNF-triggered NF-B signaling pathway by mediating cIAP recruitment independent of VCP/p97.