Akers Jared F, LaScola Michael, Bothe Adrian, Suh Hanna, Jung Carmen, Stolp Zachary D, Ghosh Tanushree, Yan Liewei L, Wang Yuming, Macurak Michelle, Devan Amisha, McKinney Mary C, Grismer Tarabryn S, Reyes Andres V, Ross Eric J, Hu Tianyi, Xu Shou-Ling, Ban Nenad, Kostova Kamena K
Carnegie Institution for Science, Department of Embryology, Baltimore, MD 21218, USA.
Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland.
Mol Cell. 2025 May 15;85(10):2048-2060.e9. doi: 10.1016/j.molcel.2025.04.017. Epub 2025 May 5.
Eukaryotic ribosome assembly is an intricate process that involves four ribosomal RNAs, 80 ribosomal proteins, and over 200 biogenesis factors that participate in numerous interdependent steps. The complexity and essentiality of this process create opportunities for deleterious mutations to occur, accumulate, and impact downstream cellular processes. "Dead-end" ribosome intermediates that result from biogenesis errors are rapidly degraded, affirming the existence of quality control (QC) pathway(s) that monitor ribosome assembly. However, the factors that differentiate between on-path and dead-end intermediates are unknown. We engineered a system to perturb ribosome assembly in human cells and discovered that faulty ribosomes are degraded via the ubiquitin-proteasome system. We identified ZNF574 as a key component of a QC pathway, which we term the ribosome assembly surveillance pathway (RASP). In an animal model, loss of ZNF574 leads to developmental defects, emphasizing the importance of RASP in organismal health.
真核生物核糖体组装是一个复杂的过程，涉及四种核糖体RNA、80种核糖体蛋白以及200多种生物发生因子，这些因子参与众多相互依赖的步骤。这个过程的复杂性和必要性为有害突变的发生、积累并影响下游细胞过程创造了机会。生物发生错误产生的“终止”核糖体中间体迅速降解，这证实了监测核糖体组装的质量控制（QC）途径的存在。然而，区分正常组装中间体和终止中间体的因子尚不清楚。我们设计了一个系统来干扰人类细胞中的核糖体组装，发现有缺陷的核糖体通过泛素-蛋白酶体系统被降解。我们确定ZNF574是QC途径的一个关键组成部分，我们将其称为核糖体组装监测途径（RASP）。在动物模型中，ZNF574的缺失会导致发育缺陷，强调了RASP在机体健康中的重要性。
