Nuclear Smad6 promotes gliomagenesis by negatively regulating PIAS3-mediated STAT3 inhibition
Nuclear Smad6 promotes gliomagenesis by negatively regulating PIAS3-mediated STAT3 inhibition
复制标题
核Smad6通过负调节PIAS3介导的STAT3抑制促进胶质瘤发生
DOI：
10.1038/s41467-018-04936-9
复制
发表时间：
2018-06-27
影响因子：
16.6
通讯作者：
Huang, Zhaohui
中科院分区：
文献类型：
--
作者：
Jiao, Jiantong;Zhang, Rui;Huang, Zhaohui
迄今为止，神经胶质瘤中组成性信号转导子和转录激活子3（STAT3）激活的分子机制尚不清楚。在这项研究中，我们报告了Smad6在胶质瘤细胞核中过表达，这与患者生存率低相关，并通过负调节活化的STAT3蛋白抑制剂（PIAS3）来调节STAT3活性。在机械上，Smad6直接与PIAS3相互作用，并且这种相互作用通过Smad6的Mad同源2（MH2）结构域和PIAS3的环结构域介导。Smad6招募Smurf1以促进PIAS3泛素化和降解，这也依赖于Smad6的MH2结构域和PY基序。因此，Smad6减少PIAS3介导的STAT3抑制并促进胶质瘤细胞生长和干细胞样细胞起始。此外，Smad6 MH2可转导蛋白恢复PIAS 3表达，随后减少胶质瘤的发生。总的来说，我们得出结论，核Smad6通过诱导PIAS3降解和随后的STAT3活性上调来增强胶质瘤的发展。
To date, the molecular mechanism underlying constitutive signal transducer and activator of transcription 3 (STAT3) activation in gliomas is largely unclear. In this study, we report that Smad6 is overexpressed in nuclei of glioma cells, which correlates with poor patient survival and regulates STAT3 activity via negatively regulating the Protein Inhibitors of Activated STAT3 (PIAS3). Mechanically, Smad6 interacts directly with PIAS3, and this interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and the Ring domain of PIAS3. Smad6 recruits Smurf1 to facilitate PIAS3 ubiquitination and degradation, which also depends on the MH2 domain and the PY motif of Smad6. Consequently, Smad6 reduces PIAS3-mediated STAT3 inhibition and promotes glioma cell growth and stem-like cell initiation. Moreover, the Smad6 MH2 transducible protein restores PIAS3 expression and subsequently reduces gliomagenesis. Collectively, we conclude that nuclear-Smad6 enhances glioma development by inducing PIAS3 degradation and subsequent STAT3 activity upregulation.