Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Science. 2017 Nov 3;358(6363). doi: 10.1126/science.aan2755.
Ribosomopathies are a group of human disorders most commonly caused by ribosomal protein haploinsufficiency or defects in ribosome biogenesis. These conditions manifest themselves as physiological defects in specific cell and tissue types. We review current molecular models to explain ribosomopathies and attempt to reconcile the tissue specificity of these disorders with the ubiquitous requirement for ribosomes in all cells. Ribosomopathies as a group are diverse in their origins and clinical manifestations; we use the well-described Diamond-Blackfan anemia (DBA) as a specific example to highlight some common features. We discuss ribosome homeostasis as an overarching principle that governs the sensitivity of specific cells and tissue types to ribosomal protein mutations. Mathematical models and experimental insights rationalize how even subtle shifts in the availability of ribosomes, such as those created by ribosome haploinsufficiency, can drive messenger RNA-specific effects on protein expression. We discuss recently identified roles played by ribosome rescue and recycling factors in regulating ribosome homeostasis.
核糖体病是一组人类疾病，最常见的原因是核糖体蛋白单倍不足或核糖体生物发生缺陷。这些情况表现为特定细胞和组织类型的生理缺陷。我们回顾了目前的分子模型来解释核糖体病，并试图将这些疾病的组织特异性与核糖体在所有细胞中普遍存在的需求协调起来。核糖体病在起源和临床表现上具有多样性；我们使用描述良好的 Diamond-Blackfan 贫血（DBA）作为一个具体的例子来突出一些共同的特征。我们讨论核糖体动态平衡作为一个总体原则，它控制着特定细胞和组织类型对核糖体蛋白突变的敏感性。数学模型和实验见解使我们能够理解，即使是核糖体可用性的微小变化，如核糖体单倍不足引起的变化，也可以驱动信使 RNA 对蛋白质表达的特异性影响。我们讨论了最近发现的核糖体拯救和再循环因子在调节核糖体动态平衡方面的作用。
