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与先天性纯红细胞再生障碍性贫血相关的核糖体蛋白缺陷会引起ATF4表达的显著改变。

Ribosomal protein deficiencies linked to Diamond-Blackfan anemia induce distinctive alterations of ATF4 expression.

作者信息

Lorenzo-Martín L Francisco, Robles-Valero Javier, Ramírez-Cota Rosa, Gaspar Sonia G, Fuentes Pedro, Gentilella Antonio, Bustelo Xosé R, Dosil Mercedes

机构信息

Centro de Investigación del Cáncer, CSIC-University of Salamanca, Campus Unamuno, 37007 Salamanca, Spain.

Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, Campus Unamuno, 37007 Salamanca, Spain.

出版信息

iScience. 2025 Mar 1;28(4):112138. doi: 10.1016/j.isci.2025.112138. eCollection 2025 Apr 18.

DOI:10.1016/j.isci.2025.112138
PMID:40406500
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12096137/
Abstract

Ribosomal protein haploinsufficiency causes Diamond-Blackfan anemia (DBA) and other ribosomopathies. DBA has been linked to p53 activation and reduced GATA1 expression, but these mechanisms do not fully explain the disease. This study unveils that deficiencies in small (RPS) or large (RPL) ribosomal subunit proteins cause a p53-independent loss of ATF4, a master regulator of stress responses and erythropoiesis, by reducing the pool of actively translating mRNAs. This defect is more pronounced in RPS deficiencies because the loss of 40S, but not 60S, subunits cause a destabilization of transcripts. downregulation occurs in early hematopoietic progenitors and correlates with the severity of erythroid differentiation defects in patients with DBA. It is also linked to the de-repression of fetal hemoglobin in erythroid cells, a frequent feature in patients with DBA. Our findings indicate that impaired expression might be a primary contributor to DBA and explain the aggravated erythroid failure of RPS-mutant patients.

摘要

核糖体蛋白单倍体不足会导致钻石黑范贫血（DBA）和其他核糖体病。DBA与p53激活和GATA1表达降低有关，但这些机制并不能完全解释该疾病。本研究揭示，小（RPS）或大（RPL）核糖体亚基蛋白的缺陷通过减少活跃翻译的mRNA池，导致p53非依赖性的ATF4缺失，ATF4是应激反应和红细胞生成的主要调节因子。这种缺陷在RPS缺陷中更为明显，因为40S亚基的缺失而非60S亚基的缺失会导致转录本的不稳定。ATF4下调发生在早期造血祖细胞中，并与DBA患者红系分化缺陷的严重程度相关。它还与红系细胞中胎儿血红蛋白的去抑制有关，这是DBA患者的常见特征。我们的研究结果表明，ATF4表达受损可能是DBA的主要原因，并解释了RPS突变患者红系衰竭加重的原因。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38fa/12096137/e1681ca88e3f/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38fa/12096137/091f0a04f454/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38fa/12096137/2138b27ce805/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38fa/12096137/0fb4cb760946/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38fa/12096137/3a5b6d8161a6/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38fa/12096137/af85fa005e2e/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38fa/12096137/32cd0b4e779d/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38fa/12096137/c35950502760/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38fa/12096137/e1681ca88e3f/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38fa/12096137/091f0a04f454/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38fa/12096137/2138b27ce805/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38fa/12096137/0fb4cb760946/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38fa/12096137/3a5b6d8161a6/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38fa/12096137/af85fa005e2e/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38fa/12096137/32cd0b4e779d/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38fa/12096137/c35950502760/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38fa/12096137/e1681ca88e3f/gr7.jpg

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本文引用的文献

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Ribosome biogenesis factors-from names to functions.核糖体生物发生因子——从名字到功能。
EMBO J. 2023 Apr 3;42(7):e112699. doi: 10.15252/embj.2022112699. Epub 2023 Feb 10.
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Animal models of Diamond-Blackfan anemia: updates and challenges.先天性再生障碍性贫血动物模型：更新与挑战。
Haematologica. 2023 May 1;108(5):1222-1231. doi: 10.3324/haematol.2022.282042.
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The homeostatic regulation of ribosome biogenesis.核糖体生物发生的体内平衡调节。
Semin Cell Dev Biol. 2023 Feb 28;136:13-26. doi: 10.1016/j.semcdb.2022.03.043. Epub 2022 Apr 16.
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ChIP-Atlas 2021 update: a data-mining suite for exploring epigenomic landscapes by fully integrating ChIP-seq, ATAC-seq and Bisulfite-seq data.ChIP-Atlas 2021 更新：通过全面整合 ChIP-seq、ATAC-seq 和 Bisulfite-seq 数据，用于探索表观基因组景观的数据挖掘套件。
Nucleic Acids Res. 2022 Jul 5;50(W1):W175-W182. doi: 10.1093/nar/gkac199.
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DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update).DAVID：一个用于基因列表功能富集分析和功能注释的网络服务器（2021 更新）。
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