title: Aberrant autolysosomal regulation is linked to the induction of embryonic senescence: differential roles of Beclin 1 and p53 in vertebrate Spns1 deficiency.
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.
authors: Department of Metabolism & Aging, The Scripps Research Institute, Jupiter, Florida, United States of America.
authors: Tomoyuki
authors: T
authors: Sasaki
authors: Department of Metabolism & Aging, The Scripps Research Institute, Jupiter, Florida, United States of America.
authors: Shanshan
authors: S
authors: Lian
authors: Department of Metabolism & Aging, The Scripps Research Institute, Jupiter, Florida, United States of America.
authors: Jie
authors: J
authors: Qi
authors: Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors: Peter E
authors: PE
authors: Bayliss
authors: Department of Earth, Atmospheric and Planetary Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors: Christopher E
authors: CE
authors: Carr
authors: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America.
authors: Jennifer L
authors: JL
authors: Johnson
authors: Department of Metabolism & Aging, The Scripps Research Institute, Jupiter, Florida, United States of America.
authors: Sujay
authors: S
authors: Guha
authors: Department of Biological Sciences, Florida Atlantic University, Jupiter, Florida, United States of America.
authors: Patrick
authors: P
authors: Kobler
authors: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America.
authors: Sergio D
authors: SD
authors: Catz
authors: Department of Metabolism & Aging, The Scripps Research Institute, Jupiter, Florida, United States of America.
authors: Matthew
authors: M
authors: Gill
authors: Department of Biological Sciences, Florida Atlantic University, Jupiter, Florida, United States of America.
authors: Kailiang
authors: K
authors: Jia
authors: Life Sciences Institute, Department of Molecular, Cellular, and Developmental Biology, Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, United States of America.
authors: Daniel J
authors: DJ
authors: Klionsky
authors: Department of Metabolism & Aging, The Scripps Research Institute, Jupiter, Florida, United States of America.
authors: Shuji
authors: S
authors: Kishi
mesh_terms: D000375:Aging / Q000235:genetics; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D001343:Autophagy / Q000235:genetics; D000071186:Beclin-1; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D018942:Macrolides / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C000598746:Becn1 protein, zebrafish; D004791:Enzyme Inhibitors; D018942:Macrolides; D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; C485184:enhanced green fluorescent protein; C454859:spns1 protein, zebrafish; C571228:tp53 protein, zebrafish; D049452:Green Fluorescent Proteins; C040929:bafilomycin A1; D025262:Vacuolar Proton-Translocating ATPases