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

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.

Keywords: Aging; Autophagy tandem sensor; Epithelial stem cells self-renewal; Hydramodel system; SBI-0206965-induced ULK1 inhibition; Whole-Body regeneration; bafilomycin-A1.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Autophagosomes / drug effects
  • Autophagosomes / enzymology*
  • Autophagosomes / genetics
  • Autophagy
  • Autophagy-Related Protein-1 Homolog / antagonists & inhibitors
  • Autophagy-Related Protein-1 Homolog / genetics
  • Autophagy-Related Protein-1 Homolog / metabolism*
  • Beclin-1 / metabolism
  • Cell Proliferation* / drug effects
  • Cell Self Renewal* / drug effects
  • Cellular Senescence* / drug effects
  • Epithelial Cells / drug effects
  • Epithelial Cells / enzymology*
  • Female
  • Gene Knockdown Techniques
  • Hydra / drug effects
  • Hydra / enzymology*
  • Hydra / genetics
  • Male
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • RNA Interference
  • Signal Transduction
  • Stem Cells / drug effects
  • Stem Cells / enzymology*


  • Beclin-1
  • Protein Kinase Inhibitors
  • Autophagy-Related Protein-1 Homolog