Aberrant Autolysosomal Regulation Is Linked to The Induction of Embryonic Senescence: Differential Roles of Beclin 1 and p53 in Vertebrate Spns1 Deficiency

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Spinster homolog 1 (Spns1) in vertebrates, as well as Spinster (Spin) in Drosophila, is a hypothetical lysosomal H+-carbohydrate transporter, which functions at a late stage of autophagy. The Spin/Spns1 defect induces aberrant autolysosome formation that leads to embryonic senescence and accelerated aging symptoms, while the molecular mechanisms of the pathogenesis are unknown in vivo. Using zebrafish, we show that Beclin 1 suppression ameliorates Spns1 loss-mediated senescence as well as autolysosomal impairment, whereas p53 deficit unexpectedly exacerbates these characteristics. We demonstrate that basal p53 activity has a certain protective role(s) against the Spns1 defect via suppressing autophagosome-lysosome fusion, while p53 activated by ultraviolet radiation amplifies the Spns1 deficit. In addition, we found that excessive lysosomal biogenesis and prolonged suboptimal acidification, modulated by v-ATPase, could be the primary reason for the appearance on the hallmarks of Spns1 deficiency. Our findings thus suggest that Spns1 is critically involved in lysosomal acidification and trafficking during autophagy, and differentially acts in a pathway with Beclin 1 and p53 in the regulation of senescence.

Vyšlo v časopise: Aberrant Autolysosomal Regulation Is Linked to The Induction of Embryonic Senescence: Differential Roles of Beclin 1 and p53 in Vertebrate Spns1 Deficiency. PLoS Genet 10(6): e32767. doi:10.1371/journal.pgen.1004409
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004409

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