Nucleolar URB1 ensures 3′ ETS rRNA removal to prevent exosome surveillance

Lin Shan, Guang Xu, Run-Wen Yao, Peng-Fei Luan, Youkui Huang, Pei-Hong Zhang, Yu-Hang Pan, Lin Zhang, Xiang Gao, Ying Li, Shi-Meng Cao, Shuai-Xin Gao, Zheng-Hu Yang, Siqi Li, Liang-Zhong Yang, Ying Wang, Catharine C. L. Wong, Li Yu, Jinsong Li, Li Yang and Ling-Ling Chen ()
Additional contact information
Lin Shan: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Guang Xu: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Run-Wen Yao: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Peng-Fei Luan: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Youkui Huang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Pei-Hong Zhang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Yu-Hang Pan: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Lin Zhang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Xiang Gao: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Ying Li: Tsinghua University
Shi-Meng Cao: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Shuai-Xin Gao: Peking University
Zheng-Hu Yang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Siqi Li: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Liang-Zhong Yang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Ying Wang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Catharine C. L. Wong: Chinese Academy of Medical Science and Peking Union Medical College
Li Yu: Tsinghua University
Jinsong Li: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Li Yang: Fudan University
Ling-Ling Chen: University of Chinese Academy of Sciences, Chinese Academy of Sciences

Nature, 2023, vol. 615, issue 7952, 526-534

Abstract: Abstract The nucleolus is the most prominent membraneless condensate in the nucleus. It comprises hundreds of proteins with distinct roles in the rapid transcription of ribosomal RNA (rRNA) and efficient processing within units comprising a fibrillar centre and a dense fibrillar component and ribosome assembly in a granular component1. The precise localization of most nucleolar proteins and whether their specific localization contributes to the radial flux of pre-rRNA processing have remained unknown owing to insufficient resolution in imaging studies2–5. Therefore, how these nucleolar proteins are functionally coordinated with stepwise pre-rRNA processing requires further investigation. Here we screened 200 candidate nucleolar proteins using high-resolution live-cell microscopy and identified 12 proteins that are enriched towards the periphery of the dense fibrillar component (PDFC). Among these proteins, unhealthy ribosome biogenesis 1 (URB1) is a static, nucleolar protein that ensures 3′ end pre-rRNA anchoring and folding for U8 small nucleolar RNA recognition and the subsequent removal of the 3′ external transcribed spacer (ETS) at the dense fibrillar component–PDFC boundary. URB1 depletion leads to a disrupted PDFC, uncontrolled pre-rRNA movement, altered pre-rRNA conformation and retention of the 3′ ETS. These aberrant 3′ ETS-attached pre-rRNA intermediates activate exosome-dependent nucleolar surveillance, resulting in decreased 28S rRNA production, head malformations in zebrafish and delayed embryonic development in mice. This study provides insight into functional sub-nucleolar organization and identifies a physiologically essential step in rRNA maturation that requires the static protein URB1 in the phase-separated nucleolus.

Date: 2023
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DOI: 10.1038/s41586-023-05767-5

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