Abstract
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.
Highlights
Since the discovery that specific genes directly regulate the lifespan of animals, two invertebrate models, the roundworm C. elegans and the fruit fly D. melanogaster, as well as the yeast S. cerevisiae, have played a key role in our understanding of the genetic mechanisms of aging (Friedman and Johnson, 1988; Cuervo, 2008)
As the ULK1 Ser/Thr kinase plays a critical role in the initiation of autophagy by phosphorylating Beclin-1 (Mizushima, 2010; Russell et al, 2013; Menon and Dhamija, 2018), we developed an in vitro kinase assay to test the activity of extracts from H. oligactis (Ho_CS) and Hydra vulgaris (Hv) on human ULK1 activity
Two main nutrient sensing pathways, TORC and AMPK, regulate the entry into autophagy through the Serine/threonine-protein kinase ULK1, which once activated, phosphorylates components of the Beclin-1 complex to initiate the formation of autophagophores, the precursors of autophagosomes (Fig. 2A) (Russell et al, 2013; Hosokawa et al, 2009; Papinski and Kraft, 2016)
Summary
Since the discovery that specific genes directly regulate the lifespan of animals, two invertebrate models, the roundworm C. elegans and the fruit fly D. melanogaster, as well as the yeast S. cerevisiae, have played a key role in our understanding of the genetic mechanisms of aging (Friedman and Johnson, 1988; Cuervo, 2008). Some or ganisms used as models in the study of the mechanisms of regeneration have been shown to be valid for the study of aging mechanisms, those equipped with large stocks of adult stem cells (Austad, 2009; Murthy and Ram, 2015). One remarkable characteristic of Hydra is their ability to withstand weeks of starvation as the cyclic activity of their stem cells is continuously maintained (Otto and Campbell, 1977; Bosch and David, 1984). In Hydra, autophagy is rapidly induced in ESCs upon star vation (Buzgariu et al, 2008; Chera et al, 2009; Galliot et al, 2018)
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