Autophagy induction is a Tor- and Tp53-independent cell survival response in a zebrafish model of disrupted ribosome biogenesis.
Autophagy induction is a Tor- and Tp53-independent cell survival response in a zebrafish model of disrupted ribosome biogenesis.
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DOI：
10.1371/journal.pgen.1003279
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Heath JK
中科院分区：
文献类型：
--
作者：
Boglev Y;Badrock AP;Trotter AJ;Du Q;Richardson EJ;Parslow AC;Markmiller SJ;Hall NE;de Jong-Curtain TA;Ng AY;Verkade H;Ober EA;Field HA;Shin D;Shin CH;Hannan KM;Hannan RD;Pearson RB;Kim SH;Ess KC;Lieschke GJ;Stainier DY;Heath JK
核糖体生物发生是细胞生长和分裂的基础。核糖体生物发生和翻译启动的中断对发育有害，是统称为核糖体疾病的一系列疾病的基础。在这里，我们描述了一个新的斑马鱼突变体，二氧化钛(Ttis450)，它在pwp2小时含有一个隐性致死突变，pwp2基因编码小亚基加工组的一种蛋白质成分。这种损伤的生化影响是成熟的18S rRNA分子产生减少，TP53激活，核糖体生物发生受损。在TTS450中，内胚层器官、眼睛、脑和颅面结构的生长严重受阻，自噬被上调，使肠道上皮细胞逃避细胞死亡。抑制Ttis450幼虫的自噬显著缩短了它们的寿命。有些令人惊讶的是，TTIS450幼虫的自噬诱导与Tor途径的状态无关，并且在TP53突变的幼虫中继续进行。这些数据表明，自噬是响应核糖体压力而启动的一种生存机制。这种反应可能与旨在通过靶向核糖体生物发生来杀死癌细胞的治疗策略有关。在某些情况下，这些治疗可能会促进自噬，并有助于癌细胞逃避细胞死亡。自噬是一种自我保护的行为，细胞通过消化自己的细胞质细胞器和蛋白质来应对应激条件，如营养枯竭和剧烈的肌肉活动，以促进其长期生存。对能够触发这种有益的细胞机制的广泛的生理刺激的理解才刚刚开始出现。然而，这一过程也有消极的一面，因为自噬在某些病理条件下被利用，包括癌症，以延长原本会死亡的细胞的寿命。我们对一种新的斑马鱼突变体二氧化钛(Ttis450)的分析进一步揭示了自噬的生理和病理后果，该突变具有消化器官缺陷和颅面结构异常。在(Ttis450)中，核糖体生产所需基因的遗传突变为受影响组织的自噬提供了强大的刺激，使它们能够逃避细胞死亡。在我们的斑马鱼模型中，核糖体生物发生受损的表型后果让人想起与一组被称为核糖体疾病的人类综合征相关的一些临床特征。
Ribosome biogenesis underpins cell growth and division. Disruptions in ribosome biogenesis and translation initiation are deleterious to development and underlie a spectrum of diseases known collectively as ribosomopathies. Here, we describe a novel zebrafish mutant, titania (ttis450), which harbours a recessive lethal mutation in pwp2h, a gene encoding a protein component of the small subunit processome. The biochemical impacts of this lesion are decreased production of mature 18S rRNA molecules, activation of Tp53, and impaired ribosome biogenesis. In ttis450, the growth of the endodermal organs, eyes, brain, and craniofacial structures is severely arrested and autophagy is up-regulated, allowing intestinal epithelial cells to evade cell death. Inhibiting autophagy in ttis450 larvae markedly reduces their lifespan. Somewhat surprisingly, autophagy induction in ttis450 larvae is independent of the state of the Tor pathway and proceeds unabated in Tp53-mutant larvae. These data demonstrate that autophagy is a survival mechanism invoked in response to ribosomal stress. This response may be of relevance to therapeutic strategies aimed at killing cancer cells by targeting ribosome biogenesis. In certain contexts, these treatments may promote autophagy and contribute to cancer cells evading cell death. Autophagy is an act of self-preservation whereby a cell responds to stressful conditions such as nutrient depletion and intense muscular activity by digesting its own cytoplasmic organelles and proteins to fuel its longer-term survival. An understanding of the wide spectrum of physiological stimuli that can trigger this beneficial cellular mechanism is only just starting to emerge. However, this process also has a negative side, since autophagy is exploited in certain pathological conditions, including cancer, to extend the lifespan of cells that would otherwise die. Our analysis of a new zebrafish mutant, titania (ttis450), with defective digestive organs and abnormal craniofacial structure, sheds further light on the physiological and pathological ramifications of autophagy. In (ttis450), an inherited mutation in a gene required for ribosome production provides a powerful stimulus to autophagy in affected tissues, allowing them to evade cell death. The phenotypic consequences of impaired ribosome biogenesis in our zebrafish model are reminiscent of some of the clinical features associated with a group of human syndromes known as ribosomopathies.
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影响因子：
11.1
作者：
He C;Klionsky DJ
通讯作者：
Klionsky DJ
AMP激活的蛋白激酶对ULK1（HATG1）的磷酸化将能量传感连接到线粒体。
DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Egan DF;Shackelford DB;Mihaylova MM;Gelino S;Kohnz RA;Mair W;Vasquez DS;Joshi A;Gwinn DM;Taylor R;Asara JM;Fitzpatrick J;Dillin A;Viollet B;Kundu M;Hansen M;Shaw RJ
通讯作者：
Shaw RJ
影响因子：
3.3
作者：
Bernstein, Kara A.;Bleichert, Franziska;Baserga, Susan J.
通讯作者：
Baserga, Susan J.
影响因子：
2.7
作者：
Farooq, Muhammad;Sulochana, K. N.;Ge, Ruowen
通讯作者：
Ge, Ruowen
影响因子：
16
作者：
Grandi, P;Rybin, V;Hurt, E
通讯作者：
Hurt, E