Tankyrase Mediates K63-Linked Ubiquitination of JNK to Confer Stress Tolerance and Influence Lifespan in Drosophila

• Published in: Cell reports (Cambridge) Vol. 25; no. 2; pp. 437 - 448
• Main Authors: Li, Ping, Huang, Ping, Li, Xiaojiao, Yin, Dingzi, Ma, Zhiwei, Wang, Hui, Song, Haiyun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.10.2018; Elsevier
• Subjects: Animals; Animals, Genetically Modified - genetics; Animals, Genetically Modified - growth & development; Animals, Genetically Modified - metabolism; Drosophila melanogaster - genetics; Drosophila melanogaster - growth & development; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; energy homeostasis; Female; JNK; K63-linked ubiquitination; lifespan; Longevity; Lysine - chemistry; Male; MAP Kinase Kinase 4 - genetics; MAP Kinase Kinase 4 - metabolism; Oxidative Stress; Poly ADP Ribosylation; Protein Processing, Post-Translational; Proteolysis; stress tolerance; Stress, Physiological; tankyrase; Tankyrases - genetics; Tankyrases - metabolism; Ubiquitination; poly-ADP-ribosylation; stress tolerance; K63-linked ubiquitination; tankyrase; JNK; lifespan; energy homeostasis
• ISSN: 2211-1247; 2211-1247
• 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. [Display omitted] •PARsylation by Tnks can induce K63-linked rather than K48-linked ubiquitination•JNK is a direct substrate of Tnks•Tnks functions as a positive regulator of JNK signaling•Loss of Tnks impairs longevity, stress tolerance, and energy storage in adult flies Poly-ADP-ribosylation of Tnks substrates is closely coupled to the ubiquitin-proteasome pathway. Li et al. reveal that Tnks can induce K63-linked ubiquitination to enhance the kinase activity of JNK. This study uncovers the physiological functions of Tnks in lifespan, stress tolerance, and energy storage via positively regulating JNK signaling.