Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Cell Rep. 2018 Oct 9;25(2):437-448. doi: 10.1016/j.celrep.2018.09.036.
Tankyrase (Tnks) transfers poly(ADP-ribose) on substrates. Whereas studies have highlighted the pivotal roles of Tnks in cancer, cherubism, systemic sclerosis, and viral infection, the requirement for Tnks under physiological contexts remains unclear. Here, we report that the loss of Tnks or its muscle-specific knockdown impairs lifespan, stress tolerance, and energy homeostasis in adult Drosophila. We find that Tnks is a positive regulator in the JNK signaling pathway, and modest alterations in the activity of JNK signaling can strengthen or suppress the Tnks mutant phenotypes. We further identify JNK as a direct substrate of Tnks. Although Tnks-dependent poly-ADP-ribosylation is tightly coupled to proteolysis in the proteasome, we demonstrate that Tnks initiates degradation-independent ubiquitination on two lysine residues of JNK to promote its kinase activity and in vivo functions. Our study uncovers a type of posttranslational modification of Tnks substrates and provides insights into Tnks-mediated physiological roles.
Tankyrase (Tnks) 将 poly(ADP-ribose) 转移到底物上。虽然研究已经强调了 Tnks 在癌症、 cherubism、系统性硬化症和病毒感染中的关键作用，但在生理环境下 Tnks 的需求仍不清楚。在这里，我们报告说，Tnks 的缺失或其肌肉特异性敲低会损害成年果蝇的寿命、应激耐受性和能量稳态。我们发现 Tnks 是 JNK 信号通路的正调节剂，并且 JNK 信号活性的适度改变可以增强或抑制 Tnks 突变表型。我们进一步鉴定 JNK 是 Tnks 的直接底物。尽管 Tnks 依赖性聚 ADP-ribosylation 与蛋白酶体中的蛋白水解紧密偶联，但我们证明 Tnks 在 JNK 的两个赖氨酸残基上启动不依赖降解的泛素化，以促进其激酶活性和体内功能。我们的研究揭示了 Tnks 底物的一种翻译后修饰类型，并为 Tnks 介导的生理作用提供了见解。
