2. Academic Validation
  3. Nucleolar URB1 ensures 3' ETS rRNA removal to prevent exosome surveillance

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

  • Nature. 2023 Mar 8. doi: 10.1038/s41586-023-05767-5.
Lin Shan # 1,  Guang Xu # 1,  Run-Wen Yao 1 2,  Peng-Fei Luan 1,  Youkui Huang 1,  Pei-Hong Zhang 3,  Yu-Hang Pan 1,  Lin Zhang 4,  Xiang Gao 1 5,  Ying Li 6,  Shi-Meng Cao 1,  Shuai-Xin Gao 7,  Zheng-Hu Yang 1 5,  Siqi Li 1,  Liang-Zhong Yang 1,  Ying Wang 1,  Catharine C L Wong 8,  Li Yu 9,  Jinsong Li 4 5 10,  Li Yang 11,  Ling-Ling Chen 12 13 14 15
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 2 Department of Biophysics and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 3 CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 4 State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 5 School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 6 Cryo EM facility, Technology Center for Protein Sciences, School of Life Science, Tsinghua University, Beijing, China.
  • 7 Center for Precision Medicine Multi-Omics Research, Peking University Health Science Center, Peking University, Beijing, China.
  • 8 Clinical Research Institute, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
  • 9 State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Centre for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China.
  • 10 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
  • 11 Center for Molecular Medicine, Children's Hospital, Fudan University and Shanghai Key Laboratory of Medical Epigenetics, International Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • 12 State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. linglingchen@sibcb.ac.cn.
  • 13 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. linglingchen@sibcb.ac.cn.
  • 14 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. linglingchen@sibcb.ac.cn.
  • 15 New Cornerstone Science Laboratory, Shenzhen, China. linglingchen@sibcb.ac.cn.
  • # Contributed equally.
PMID: 36890225 DOI: 10.1038/s41586-023-05767-5
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.

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