Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Keith Peters Building, Hills Rd, Cambridge, CB2 0XY, UK.
Wellcome Trust-Medical Research Council Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Puddicombe Way, Cambridge Biomedical Campus, Cambridge, CB2 0AW, UK.
Nat Commun. 2022 Mar 23;13(1):1562. doi: 10.1038/s41467-022-29214-7.
Protein synthesis is a cyclical process consisting of translation initiation, elongation, termination and ribosome recycling. The release factors SBDS and EFL1-both mutated in the leukemia predisposition disorder Shwachman-Diamond syndrome - license entry of nascent 60S ribosomal subunits into active translation by evicting the anti-association factor eIF6 from the 60S intersubunit face. We find that in mammalian cells, eIF6 holds all free cytoplasmic 60S subunits in a translationally inactive state and that SBDS and EFL1 are the minimal components required to recycle these 60S subunits back into additional rounds of translation by evicting eIF6. Increasing the dose of eIF6 in mice in vivo impairs terminal erythropoiesis by sequestering post-termination 60S subunits in the cytoplasm, disrupting subunit joining and attenuating global protein synthesis. These data reveal that ribosome maturation and recycling are dynamically coupled by a mechanism that is disrupted in an inherited leukemia predisposition disorder.
蛋白质合成是一个循环过程，包括翻译起始、延伸、终止和核糖体回收。释放因子 SBDS 和 EFL1 在白血病易感性疾病 Shwachman-Diamond 综合征中均发生突变，它们通过从 60S 亚基间界面驱逐抗关联因子 eIF6，从而允许新生的 60S 核糖体亚基进入活跃的翻译。我们发现，在哺乳动物细胞中，eIF6 将所有游离的细胞质 60S 亚基保持在翻译失活状态，而 SBDS 和 EFL1 是将这些 60S 亚基回收到后续翻译循环中所必需的最小组件，通过驱逐 eIF6。体内增加 eIF6 的剂量会通过将翻译后 60S 亚基隔离在细胞质中，破坏亚基连接并减弱全局蛋白质合成，从而损害终末红细胞生成。这些数据表明，核糖体成熟和回收通过一种机制动态偶联，该机制在遗传性白血病易感性疾病中被破坏。
