HLA-B-associated transcript 3 (Bat3) stabilizes and activates p53 in a HAUSP-dependent manner
HLA-B-associated transcript 3 (Bat3) stabilizes and activates p53 in a HAUSP-dependent manner
复制标题
HLA-B 相关转录物 3 (Bat3) 以 HAUSP 依赖性方式稳定并激活 p53
DOI：
10.1093/jmcb/mjz102
复制
发表时间：
2019-10
影响因子：
5.5
通讯作者：
Tang Jun
中科院分区：
文献类型：
--
作者：
Zhang Rui;Cui Di;Xue Teng;Lang Yue;Zhang Yunfan;Li Lianjie;Sun Haili;Kuang Yu;Li Gebin;Tang Jun
摘要P53通路是一个高度复杂的信号网络，包含多个关键调控因子。Hausp是P53途径的关键组成部分，它作为P53及其关键抑制因子MDM2的脱泛素酶。在这里，我们鉴定了一种新的Hausp相互作用蛋白，人类白细胞抗原B相关转录本3(BAT3)，并发现它能够通过Hausp依赖的机制诱导P53的稳定和激活，导致细胞生长抑制。令人惊讶的是，Hausp的去泛素化酶活性并不是这种现象所必需的。免疫共沉淀显示P53与BAT3和Hausp在体内共存，HAUSP可能作为结合介质增强P53和BAT3之间的相互作用。进一步的研究表明，这种三蛋白复合体的形成干扰了P53与其蛋白酶体受体S5a的结合，并促进了P53在细胞核内的积聚。值得注意的是，在Hausp存在的情况下，MDM2蛋白的丰度也受到BAT3的调节。BAT3和Hausp的过表达增加了MDM2的蛋白水平，但不影响P53-MDM2的相互作用和MDM2介导的P53泛素化，表明BAT3-HAUSP介导的蛋白稳定不是P53所特有的，BAT3介导的P53-MDM2途径的调节可能涉及不同的机制。总之，我们的研究揭示了一种新的机制，即通过Hausp介导的与BAT3的相互作用来稳定和激活P53，并暗示BAT3可能通过稳定P53而发挥肿瘤抑制作用。
Abstract The p53 pathway is a highly complex signaling network including several key regulators. HAUSP is a critical component of the p53 pathway acting as a deubiquitinase for both p53 and its key repressor Mdm2. Here, we identified a novel HAUSP-interacting protein, HLA-B-associated transcript 3 (Bat3) and found it to be capable of inducing p53 stabilization and activation via a HAUSP-dependent mechanism, resulting in cell growth inhibition. Surprisingly, the deubiquitylating enzymatic activity of HAUSP was not required for this phenomenon. Co-immunoprecipitation showed that p53 coexisted in a complex with Bat3 and HAUSP in vivo, and HAUSP may serve as a binding mediator to enhance the interaction between p53 and Bat3. Further studies revealed that formation of this three-protein complex interfered with the binding of p53 to its proteasome receptor S5a and promoted the accumulation of p53 in nucleus. Notably, Mdm2 protein abundance is also regulated by Bat3 in the presence of HAUSP. Overexpression of Bat3 and HAUSP increases Mdm2 protein levels without influencing the p53–Mdm2 interaction and Mdm2-mediated p53 ubiquitination, indicating that Bat3–HAUSP-mediated protein stabilization is not specific to p53 and different mechanisms may be involved in Bat3-mediated regulation of p53–Mdm2 pathway. Together, our study unravels a novel mechanism by which p53 is stabilized and activated by HAUSP-mediated interaction with Bat3 and implies that Bat3 might function as a tumor suppressor through the stabilization of p53.
登录
查看更多内容
DOI：
10.1111/febs.13618
发表时间：
2016-02
期刊：
The FEBS Journal
影响因子：
--
作者：
Hirofumi Tanaka;Toshiki Takahashi;Yiming Xie;R. Minami;Y. Yanagi;Mizuki Hayashishita;R. Suzuki;Naoto Yokota;M. Shimada;T. Mizushima;N. Kuwabara;R. Kato;H. Kawahara
通讯作者：
Hirofumi Tanaka;Toshiki Takahashi;Yiming Xie;R. Minami;Y. Yanagi;Mizuki Hayashishita;R. Suzuki;Naoto Yokota;M. Shimada;T. Mizushima;N. Kuwabara;R. Kato;H. Kawahara
影响因子：
8.8
作者：
Xu Y;Cai M;Yang Y;Huang L;Ye Y
通讯作者：
Ye Y
影响因子：
3.3
作者：
Schmid SL;Carnes M;Goodenough U;Hopkins N;Leboy P;Masur S;Valian V;ASCB Women in Cell Biology Committee
通讯作者：
ASCB Women in Cell Biology Committee
影响因子：
21.3
作者：
Epping, Mirjam T.;Meijer, Lars A. T.;Bernards, Rene
通讯作者：
Bernards, Rene
影响因子：
4.3
作者：
Meulmeester, E;Pereg, Y;Jochemsen, AG
通讯作者：
Jochemsen, AG