Ribosomal protein mutations induce autophagy through S6 kinase inhibition of the insulin pathway.
Ribosomal protein mutations induce autophagy through S6 kinase inhibition of the insulin pathway.
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DOI：
10.1371/journal.pgen.1004371
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发表时间：
2014
期刊：
影响因子：
4.5
通讯作者：
MacInnes AW
中科院分区：
文献类型：
--
作者：
Heijnen HF;van Wijk R;Pereboom TC;Goos YJ;Seinen CW;van Oirschot BA;van Dooren R;Gastou M;Giles RH;van Solinge W;Kuijpers TW;Gazda HT;Bierings MB;Da Costa L;MacInnes AW
影响核糖体的突变会导致几种称为核糖体病变的疾病，其表型包括生长缺陷、细胞减少和骨髓衰竭。例如，钻石-布莱克凡贫血(DBA)是一种与核糖体蛋白(RP)基因突变有关的纯红细胞再生障碍性贫血。在这里，我们展示了DBA连接的RPS19基因的敲除诱导了自噬的细胞自我消化过程，这是正常造血的关键途径。我们还观察到DBA患者来源的细胞、RPS19基因敲除的CD34+红细胞前体细胞、RP缺乏的斑马鱼胚胎的红细胞以及Shwachman-Diamond综合征(SDS)患者的细胞自噬增加。在所有这些模型中，RPS的丢失导致S6激酶磷酸化显着增加，我们发现这是由活性氧物种(ROS)的增加所触发的。我们发现，S6激酶磷酸化的增加抑制了胰岛素途径和AKT的磷酸化活性，其机制使人联想到胰岛素抵抗。虽然用胰岛素刺激RP缺陷细胞会减少自噬，但抗氧化剂治疗会减少S6激酶的磷酸化、自噬和P53肿瘤抑制因子的稳定。我们的数据表明，RP丢失通过增加细胞内ROS水平促进S6激酶和P53的异常激活。这些信号通路的失控很可能在核糖体疾病的病理生理学中起着重要作用。与影响核糖体的突变有关的疾病，即核糖病，具有异常广泛的表型。然而，许多核糖病都有一些共同的特征，包括细胞减少和生长缺陷。我们的研究旨在阐明这些常见表型背后的机制。我们发现，核糖体蛋白基因的突变会导致一系列异常信号事件，导致细胞开始回收和消耗自己的细胞内内容。这种分解代谢的基本机制在细胞缺乏营养时被激活，也在血细胞成熟的严格调控过程中激活。这一机制的解除为血细胞受到损害核糖体的基因突变如此剧烈的影响提供了一种解释。此外，我们发现激活这种分解代谢的信号与高度保守的胰岛素信号通路的损害有关，而胰岛素信号通路是生长所必需的。综上所述，我们对影响核糖体的突变所涉及的途径的深入描述增加了我们对这些疾病的病因学的理解，并开辟了以前未知的潜在治疗途径。
Mutations affecting the ribosome lead to several diseases known as ribosomopathies, with phenotypes that include growth defects, cytopenia, and bone marrow failure. Diamond-Blackfan anemia (DBA), for example, is a pure red cell aplasia linked to the mutation of ribosomal protein (RP) genes. Here we show the knock-down of the DBA-linked RPS19 gene induces the cellular self-digestion process of autophagy, a pathway critical for proper hematopoiesis. We also observe an increase of autophagy in cells derived from DBA patients, in CD34+ erythrocyte progenitor cells with RPS19 knock down, in the red blood cells of zebrafish embryos with RP-deficiency, and in cells from patients with Shwachman-Diamond syndrome (SDS). The loss of RPs in all these models results in a marked increase in S6 kinase phosphorylation that we find is triggered by an increase in reactive oxygen species (ROS). We show that this increase in S6 kinase phosphorylation inhibits the insulin pathway and AKT phosphorylation activity through a mechanism reminiscent of insulin resistance. While stimulating RP-deficient cells with insulin reduces autophagy, antioxidant treatment reduces S6 kinase phosphorylation, autophagy, and stabilization of the p53 tumor suppressor. Our data suggest that RP loss promotes the aberrant activation of both S6 kinase and p53 by increasing intracellular ROS levels. The deregulation of these signaling pathways is likely playing a major role in the pathophysiology of ribosomopathies. Diseases linked to mutations affecting the ribosome, ribosomopathies, have an exceptionally wide range of phenotypes. However, many ribosomopathies have some features in common including cytopenia and growth defects. Our study aims to clarify the mechanisms behind these common phenotypes. We find that mutations in ribosomal protein genes result in a series of aberrant signaling events that cause cells to start recycling and consuming their own intracellular contents. This basic mechanism of catabolism is activated when cells are starving for nutrients, and also during the tightly regulated process of blood cell maturation. The deregulation of this mechanism provides an explanation as to why blood cells are so acutely affected by mutations in genes that impair the ribosome. Moreover, we find that the signals activating this catabolism are coupled to impairment of the highly conserved insulin-signaling pathway that is essential for growth. Taken together, our in-depth description of the pathways involved as the result of mutations affecting the ribosome increases our understanding about the etiology of these diseases and opens up previously unknown avenues of potential treatment.
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影响因子：
3.9
作者：
Boria, Ilenia;Garelli, Emanuela;Gazda, Hanna T.;Aspesi, Anna;Quarello, Paola;Pavesi, Elisa;Ferrante, Daniela;Meerpohl, Joerg J.;Kartal, Mutlu;Da Costa, Lydie;Proust, Alexis;Leblanc, Thierry;Simansour, Maud;Dahl, Niklas;Froejmark, Anne-Sophie;Pospisilova, Dagmar;Cmejla, Radek;Beggs, Alan H.;Sheen, Mee R.;Landowski, Michael;Buros, Christopher M.;Clinton, Catherine M.;Dobson, Lori J.;Vlachos, Adrianna;Atsidaftos, Eva;Lipton, Jeffrey M.;Ellis, Steven R.;Ramenghi, Ugo;Dianzani, Irma
通讯作者：
Dianzani, Irma
影响因子：
6.5
作者：
Danilova N;Sakamoto KM;Lin S
通讯作者：
Lin S
影响因子：
15.9
作者：
Bellodi, Cristian;Lidonnici, Maria Rosa;Calabretta, Bruno
通讯作者：
Calabretta, Bruno
影响因子：
4.8
作者：
Ding, Wen-Xing;Li, Min;Yin, Xiao-Ming
通讯作者：
Yin, Xiao-Ming
影响因子：
4.8
作者：
Barthel, A;Okino, ST;Roth, RA
通讯作者：
Roth, RA