Cotranslational molecular condensation of cochaperones and assembly factors facilitates axonemal dynein biogenesis

• 成果类型: Article
• 署名作者: Li, Yuanyuan; Xu, Wenyan; Cheng, Yubao; Djenoune, Lydia; Zhuang, Chuzhi; Cox, Andrew Lee; Britto, Clemente J.; Yuan, Shiaulou; Wang, Siyuan; Sun, Zhaoxia
• 署名单位: Yale University; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Yale University; Yale University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13888
• DOI: 10.1073/pnas.2402818121
• 发表日期: 2024-11-19
• 关键词: protein complex; sensory cilia; mutations; permeability; drosophila; interacts; zmynd10; screen; inner; arms

摘要

Axonemal dynein, the macromolecular machine that powers ciliary motility, assembles in the cytosol with the help of dynein axonemal assembly factors (DNAAFs). These DNAAFs localize in cytosolic foci thought to form via liquid-liquid phase separation. However, the functional significance of DNAAF foci formation and how the production and assembly of multiple components are so efficiently coordinated, at such enormous scale, remain unclear. Here, we unveil an axonemal dynein production and assembly hub enriched with translating heavy chains (HCs) and DNAAFs. We show that mRNAs encoding interacting HCs of outer dynein arms colocalize in cytosolic foci, along with nascent HCs. The formation of these mRNA foci and their colocalization relies on HC translation. We observe that a previously identified DNAAF assembly, containing the DNAAF Lrrc6 and cochaperones Ruvbl1 and Ruvbl2, colocalizes with these HC foci, and is also dependent on HC translation. We additionally show that Ruvbl1 is required for the recruitment of Lrrc6 into the HC foci and that both proteins function cotranslationally. We propose that these DNAAF foci are anchored by stable interactions between translating HCs, ribosomes, and encoding mRNAs, followed by cotranslational molecular condensation of cochaperones and assembly factors, providing a potential mechanism that coordinates HC translation, folding, and assembly at scale.