The ULK1 kinase, a necessary component of the pro-regenerative and anti-aging machinery in Hydra

Article Article scientifique Article The ULK1 kinase, a necessary component of the pro-regenerative and anti-aging machinery in Hydra eng 2021 author Suknovic Nenad Slavko 813769 author Tomczyk Szymon 743605 author Colevret Delphine 913523 author Perruchoud Chrystelle 676031 author Galliot Brigitte 0000-0001-7596-8284 29979 10.1016/j.mad.2020.111414 33338499 0047-6374 https://linkinghub.elsevier.com/retrieve/pii/S0047637420302104 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. Hydramodel system Aging Whole-Body regeneration Autophagy tandem sensor Epithelial stem cells self-renewal SBI-0206965-induced ULK1 inhibition bafilomycin-A1 Dewey 590 Swiss National Science Foundation Developmental and cellular mechanisms that underlie regeneration and slow aging in Hydra 310030_189122 CH Project funding Swiss National Science Foundation 31003_169930; 310030_189122 CH 23 Institut de génétique et de génomique 0DH 44 Département de génétique et évolution 162 false 821 Groupe Galliot Mechanisms of Ageing and Development 194 111414 5adddd00-4666-4601-84c6-7e8ecfb350b2 Article (Published version) Public 2021_Suknovic_ULK1-aging-regeneration_MAD.pdf 13463459 application/pdf CC BY e3272de0-0e3b-416a-9731-7c38f07ec82d Appendix Public 2021_Suknovic_ULK1_MAD_supplt.pdf 3554757 application/pdf CC BY 17ffd829-7190-413f-9485-149c273948a3 Summary Public 2021_Suknovic_ULK1_MAD_graphical_abstract.jpg 26209 image/jpeg CC BY openAccess Centres et instituts / Institut de génétique et de génomique Faculté des sciences / Section de biologie / Département de génétique et évolution

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The ULK1 kinase, a necessary component of the pro-regenerative and anti-aging machinery in Hydra	Mechanisms of Ageing and Development			2021	425	314

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Colevret, Delphine