Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, QC H3C 3J7, Canada.
Mol Cell. 2024 Jun 20;84(12):2337-2352.e9. doi: 10.1016/j.molcel.2024.05.018. Epub 2024 Jun 12.
Ribosome assembly requires precise coordination between the production and assembly of ribosomal components. Mutations in ribosomal proteins that inhibit the assembly process or ribosome function are often associated with ribosomopathies, some of which are linked to defects in proteostasis. In this study, we examine the interplay between several yeast proteostasis enzymes, including deubiquitylases (DUBs) Ubp2 and Ubp14, and E3 ligases Ufd4 and Hul5, and we explore their roles in the regulation of the cellular levels of K29-linked unanchored polyubiquitin (polyUb) chains. Accumulating K29-linked unanchored polyUb chains associate with maturing ribosomes to disrupt their assembly, activate the ribosome assembly stress response (RASTR), and lead to the sequestration of ribosomal proteins at the intranuclear quality control compartment (INQ). These findings reveal the physiological relevance of INQ and provide insights into mechanisms of cellular toxicity associated with ribosomopathies.
核糖体组装需要核糖体成分的产生和组装之间的精确协调。核糖体蛋白的突变会抑制组装过程或核糖体功能，这些突变通常与核糖体病有关，其中一些与蛋白质稳态缺陷有关。在这项研究中，我们研究了几种酵母蛋白质稳态酶之间的相互作用，包括去泛素化酶（DUB）Ubp2 和 Ubp14，以及 E3 连接酶 Ufd4 和 Hul5，并探讨了它们在调节细胞内 K29 连接的无锚定多泛素（polyUb）链水平中的作用。积累的 K29 连接的无锚定多泛素链与成熟的核糖体结合，破坏它们的组装，激活核糖体组装应激反应（RASTR），并导致核糖体蛋白在内核质量控制区室（INQ）中的隔离。这些发现揭示了 INQ 的生理相关性，并提供了对与核糖体病相关的细胞毒性机制的深入了解。
