SUMOylation represses the transcriptional activity of the Unfolded Protein Response transducer ATF6.
SUMOylation represses the transcriptional activity of the Unfolded Protein Response transducer ATF6.
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SUMO 化可抑制未折叠蛋白响应传感器 ATF6 的转录活性。
DOI：
10.1016/j.bbrc.2017.10.103
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发表时间：
2017-12
期刊：
影响因子：
--
通讯作者：
Xia Hou
中科院分区：
文献类型：
--
作者：
Xia Hou
未折叠蛋白反应（Unfolded Protein Response，UPR）是内质网（Endoplasmic Reticulum，ER）释放的一系列细胞内应激信号，保护细胞免受因内质网中未折叠或错误折叠蛋白积累而引起的应激。转录激活因子6（Activating transcription factor 6，ATF 6）是不饱和蛋白受体（UPR）的主要转导因子之一，通过转录调控对应激细胞进行重构。虽然ATF 6的激活机制和生物学作用已经得到了很好的研究，但对ATF 6的负或反馈调节仍然很难理解。在这份报告中，我们表明，ATF 6蛋白可以被修饰的小泛素样修饰（SUMO化）和转录活性的ATF 6是负调控SUMO化。我们发现，在表达由突变型人类囊性纤维化跨膜传导调节因子（CFTR）基因（dF 508 CFTR）编码的错误折叠的CFTR的细胞中，ATF 6的SUMO化显著增加。进一步的分析显示，在人、小鼠和大鼠的ATF 6蛋白的反式激活结构域中存在两个高度保守的SUMO化基序。人ATF 6蛋白可以通过小泛素样修饰蛋白1（SUMO-1）和E3 SUMO蛋白连接酶1（PIAS 1）介导在位于ATF 6蛋白活化形式N-末端的保守SUMO化残基Lys 149处SUMO化。双分子荧光互补（BiFC）分析证实，激活的ATF 6蛋白可以被SUMO化，并且ATF 6 SUMO化发生在细胞核中。此外，反式激活报告分析表明，在保守残基Lys 149处的ATF 6蛋白的SUMO化抑制ATF 6的转录活性。总之，我们的研究揭示了UPR转导子ATF 6通过翻译后SUMO化的负调控。这项研究的信息不仅将增加我们对UPR信号转导的微调调节的理解，而且还将为UPR的治疗益处的调节提供信息。
The Unfolded Protein Response (UPR) is a cascade of intracellular stress signaling from the endoplasmic reticulum (ER) that protect the cells from the stress caused by accumulation of unfolded or misfolded proteins in the ER. Activating transcription factor 6 (ATF6) is one of primary UPR transducers that remodels the stressed cells through transcriptional regulation. Although the activation mechanism and biological roles of ATF6 have been well studied, the understanding of the negative or feedback regulation of ATF6 remains elusive. In this report, we showed that ATF6 protein can be modified by small ubiquitin-like modification (SUMOylation) and that the transcriptional activity of ATF6 is negatively regulated by SUMOylation. We identified that SUMOylation of ATF6 is significantly increased in the cells expressing misfolded cystic fibrosis transmembrane conductance regulator (CFTR) encoded by the mutant humanCFTRgene (dF508CFTR). Further analyses revealed two highly conserved SUMOylation motifs within thetrans-activation domain of ATF6 protein of human, mouse, or rat specie. The human ATF6 protein can be SUMOylated mediated through the small ubiquitin-like modifier protein 1 (SUMO-1) and E3 SUMO-protein ligase 1 (PIAS1) at the conserved sumoylation residue Lys149that is located at the N-terminal of the activated form of ATF6 protein. Bimolecular fluorescence complementation (BiFC) analysis confirmed that the activated ATF6 protein can be SUMOylated and that the ATF6 sumoylation occurs in the nuclei. Moreover,trans-activation reporter analysis demonstrated that SUMOylation of the ATF6 protein at the conserved residue Lys149represses the transcriptional activity of ATF6. In summary, our study revealed a negative regulation of the UPR transducer ATF6 through post-translational SUMOylation. The information from this study will not only increase our understanding of the fine-tuning regulation of the UPR signaling but will also be informative to the modulation of the UPR for therapeutic benefits.
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