Aberrant autolysosomal regulation is linked to the induction of embryonic senescence: differential roles of Beclin 1 and p53 in vertebrate Spns1 deficiency.
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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DOI：
10.1371/journal.pgen.1004409
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发表时间：
2014-06
期刊：
影响因子：
4.5
通讯作者：
Kishi S
中科院分区：
文献类型：
--
作者：
Sasaki T;Lian S;Qi J;Bayliss PE;Carr CE;Johnson JL;Guha S;Kobler P;Catz SD;Gill M;Jia K;Klionsky DJ;Kishi S
果蝇中的Spinster（Spin）或脊椎动物中的Spinster homolog 1（Spns 1）是一种假定的溶酶体H+-碳水化合物转运蛋白，在自噬的晚期发挥作用。Spin/Spns 1缺陷诱导异常自溶体形成，导致胚胎衰老和加速衰老症状，但对导致体内发病机制知之甚少。Beclin 1和p53是两个关键的肿瘤抑制因子，其关键地参与自噬过程及其调节。使用斑马鱼作为遗传模型，我们发现Beclin 1抑制改善了Spns 1丢失介导的衰老以及自噬损伤，而出乎意料的是，p53缺陷加剧了这两个特征。我们证明，“基础p53”活性通过抑制自噬、溶酶体生物发生和随后的自溶酶体形成和成熟对Spns 1缺陷诱导的衰老起一定的保护作用，并且p53损失可以抵消Beclin 1抑制的效果以挽救Spns 1缺陷。相比之下，在响应DNA损伤，“激活的p53”表现出明显的增强Spns 1缺陷的表型，诱导自噬和凋亡。此外，我们发现，溶酶体酸化和生物合成介导的空泡型H+-ATP酶，以及随后的自噬体-溶酶体融合的化学和遗传阻断，防止出现的标志所造成的Spns 1缺陷，无论基础p53状态。因此，这些结果提供了Spns 1在自噬和衰老过程中与Beclin 1和p53不同的证据。脊椎动物中的Spinster同系物1（Spns 1）以及果蝇中的Spinster（Spin）是一种假设的溶酶体H+-碳水化合物转运蛋白，其在自噬的晚期发挥作用。Spin/Spns 1缺陷诱导异常自溶体形成，导致胚胎衰老和加速衰老症状，而发病机制的分子机制在体内是未知的。使用斑马鱼，我们表明，Beclin 1抑制改善Spns 1损失介导的衰老以及自溶酶体损伤，而p53缺陷意外地加剧了这些特征。我们证明基础p53活性通过抑制自噬体-溶酶体融合对Spns 1缺陷具有一定的保护作用，而紫外线辐射激活的p53放大了Spns 1缺陷。此外，我们发现，过度的溶酶体生物合成和延长的次优酸化，由v-ATP酶调节，可能是出现Spns 1缺陷的标志的主要原因。因此，我们的研究结果表明，Spns 1是至关重要的参与溶酶体酸化和自噬过程中的运输，并在衰老的调节与Beclin 1和p53的通路中发挥差异作用。
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. 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.
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DOI：
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发表时间：
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影响因子：
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