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ZIRC
ZFIN ID: ZDB-PUB-140627-9
Aberrant Autolysosomal Regulation Is Linked to The Induction of Embryonic Senescence: Differential Roles of Beclin 1 and p53 in Vertebrate Spns1 Deficiency
Sasaki, T., Lian, S., Qi, J., Bayliss, P.E., Carr, C.E., Johnson, J.L., Guha, S., Kobler, P., Catz, S.D., Gill, M., Jia, K., Klionsky, D.J., Kishi, S.
Date: 2014
Source: PLoS Genetics   10: e1004409 (Journal)
Registered Authors: Bayliss, Peter, Kishi, Shuji
Keywords: Lysosomes, Zebrafish, Embryos, Autophagic cell death, Biosynthesis, Senescence, Apoptosis, Eyes
MeSH Terms:
  • Aging/genetics
  • Animals
  • Apoptosis Regulatory Proteins/antagonists & inhibitors*
  • Apoptosis Regulatory Proteins/genetics
  • Autophagy/genetics
  • DNA Damage/genetics
  • DNA Repair/genetics
  • Enzyme Inhibitors/pharmacology
  • Gene Knockdown Techniques
  • Green Fluorescent Proteins/genetics
  • Lysosomes/genetics
  • Lysosomes/metabolism*
  • Macrolides/pharmacology
  • Membrane Proteins/genetics*
  • Mitochondria/genetics
  • Mitochondria/metabolism
  • Tumor Suppressor Protein p53/genetics*
  • Vacuolar Proton-Translocating ATPases/antagonists & inhibitors
  • Vacuolar Proton-Translocating ATPases/metabolism*
  • Zebrafish
  • Zebrafish Proteins/antagonists & inhibitors*
  • Zebrafish Proteins/genetics*
PubMed: 24967584 Full text @ PLoS Genet.
FIGURES
ABSTRACT
Spinster (Spin) in Drosophila or Spinster homolog 1 (Spns1) in vertebrates is a putative 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, but little is known about the mechanisms leading to the pathogenesis in vivo. Beclin 1 and p53 are two pivotal tumor suppressors that are critically involved in the autophagic process and its regulation. Using zebrafish as a genetic model, we show that Beclin 1 suppression ameliorates Spns1 loss-mediated senescence as well as autophagic impairment, whereas unexpectedly p53 deficit exacerbates both of these characteristics. We demonstrate that 'basal p53' activity plays a certain protective role(s) against the Spns1 defect-induced senescence via suppressing autophagy, lysosomal biogenesis, and subsequent autolysosomal formation and maturation, and that p53 loss can counteract the effect of Beclin 1 suppression to rescue the Spns1 defect. By contrast, in response to DNA damage, 'activated p53' showed an apparent enhancement of the Spns1-deficient phenotype, by inducing both autophagy and apoptosis. Moreover, we found that a chemical and genetic blockage of lysosomal acidification and biogenesis mediated by the vacuolar-type H+-ATPase, as well as of subsequent autophagosome-lysosome fusion, prevents the appearance of the hallmarks caused by the Spns1 deficiency, irrespective of the basal p53 state. Thus, these results provide evidence that Spns1 operates during autophagy and senescence differentially with Beclin 1 and p53.
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