Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Medical Physiology, University Medical Center Utrecht, Utrecht, 3584 CM, Netherlands.
Sci Signal. 2021 Feb 23;14(671):eabd2639. doi: 10.1126/scisignal.abd2639.
Ribosome biogenesis in eukaryotes requires the coordinated production and assembly of 80 ribosomal proteins and four ribosomal RNAs (rRNAs), and its rate must be synchronized with cellular growth. Here, we showed that the Microprocessor complex, which mediates the first step of microRNA processing, potentiated the transcription of ribosomal protein genes by eliminating DNA/RNA hybrids known as R-loops. Nutrient deprivation triggered the nuclear export of Drosha, a key component of the Microprocessor complex, and its subsequent degradation by the E3 ubiquitin ligase Nedd4, thereby reducing ribosomal protein production and protein synthesis. In mouse erythroid progenitors, conditional deletion of led to the reduced production of ribosomal proteins, translational inhibition of the mRNA encoding the erythroid transcription factor Gata1, and impaired erythropoiesis. This phenotype mirrored the clinical presentation of human "ribosomopathies." Thus, the Microprocessor complex plays a pivotal role in synchronizing protein synthesis capacity with cellular growth rate and is a potential drug target for anemias caused by ribosomal insufficiency.
真核生物的核糖体生物发生需要协调 80 种核糖体蛋白和 4 种核糖体 RNA（rRNA）的产生和组装，其速度必须与细胞生长同步。在这里，我们表明，介导 microRNA 加工第一步的 Microprocessor 复合物通过消除称为 R 环的 DNA/RNA 杂交体来增强核糖体蛋白基因的转录。营养剥夺触发了 Microprocessor 复合物的关键组成部分 Drosha 的核输出，以及随后被 E3 泛素连接酶 Nedd4 降解，从而减少核糖体蛋白的产生和蛋白质合成。在小鼠红系祖细胞中，条件性缺失 导致核糖体蛋白产生减少，编码红系转录因子 Gata1 的 mRNA 翻译抑制，以及红细胞生成受损。这种表型与人类“核糖体病”的临床表现相似。因此，Microprocessor 复合物在协调蛋白质合成能力与细胞生长速率方面起着关键作用，是由核糖体不足引起的贫血的潜在药物靶点。
