Department of Genetics and Evolution, Institute of Genetics and Genomics in Geneva (iGE3), Faculty of Sciences, University of Geneva, 30 Quai Ernest Ansermet, CH-1211, Geneva 4, Switzerland.
Department of Genetics and Evolution, Institute of Genetics and Genomics in Geneva (iGE3), Faculty of Sciences, University of Geneva, 30 Quai Ernest Ansermet, CH-1211, Geneva 4, Switzerland.
Mech Ageing Dev. 2021 Mar;194:111414. doi: 10.1016/j.mad.2020.111414. Epub 2020 Dec 15.
Hydra vulgaris (Hv) has a high regenerative potential and negligible senescence, as its stem cell populations divide continuously. In contrast, the cold-sensitive H. oligactis (Ho_CS) rapidly develop an aging phenotype under stress, with epithelial stem cells deficient for autophagy, unable to maintain their self-renewal. Here we tested in aging, non-aging and regenerating Hydra the activity and regulation of the ULK1 kinase involved in autophagosome formation. In vitro kinase assays show that human ULK1 activity is activated by Hv extracts but repressed by Ho_CS extracts, reflecting the ability or inability of their respective epithelial cells to initiate autophagosome formation. The factors that keep ULK1 inactive in Ho_CS remain uncharacterized. Hv_Basel1 animals exposed to the ULK1 inhibitor SBI-0206965 no longer regenerate their head, indicating that the sustained autophagy flux recorded in regenerating Hv_AEP2 transgenic animals expressing the DsRed-GFP-LC3A autophagy tandem sensor is necessary. The SBI-0206965 treatment also alters the contractility of intact Hv_Basel1 animals, and leads to a progressive reduction of animal size in Hv_AEP2, similarly to what is observed in ULK1(RNAi) animals. We conclude that the evolutionarily-conserved role of ULK1 in autophagy initiation is crucial to maintain a dynamic homeostasis in Hydra, which supports regeneration efficiency and prevents aging.
普通Hydra（Hv）具有较高的再生潜能和较低的衰老率，因为其干细胞群体持续分裂。相比之下，冷敏感 Hydra（Ho_CS）在应激下会迅速出现衰老表型，上皮干细胞缺乏自噬，无法维持自我更新。在这里，我们在衰老、非衰老和再生的 Hydra 中测试了参与自噬体形成的 ULK1 激酶的活性和调节。体外激酶测定表明，人 ULK1 活性被 Hv 提取物激活，但被 Ho_CS 提取物抑制，反映了它们各自的上皮细胞启动自噬体形成的能力或无能。使 Ho_CS 中 ULK1 失活的因素仍未被阐明。暴露于 ULK1 抑制剂 SBI-0206965 的 Hv_Basel1 动物不再再生头部，表明在表达 DsRed-GFP-LC3A 自噬串联传感器的再生 Hv_AEP2 转基因动物中记录的持续自噬通量是必要的。SBI-0206965 处理还改变了完整 Hv_Basel1 动物的收缩性，并导致 Hv_AEP2 动物的体型逐渐减小，这与在 ULK1(RNAi)动物中观察到的情况类似。我们得出结论，ULK1 在自噬体起始中的进化保守作用对于维持 Hydra 的动态平衡至关重要，这支持了再生效率并防止了衰老。
