NRDE2 negatively regulates exosome functions by inhibiting MTR4 recruitment and exosome interaction
- Jianshu Wang1,2,9,
- Jiyun Chen3,9,
- Guifen Wu1,2,9,
- Hongling Zhang2,4,9,
- Xian Du5,9,
- Suli Chen1,2,
- Li Zhang1,2,
- Ke Wang1,2,
- Jing Fan1,2,
- Shuaixin Gao6,
- Xudong Wu7,
- Shouxiang Zhang3,
- Bin Kuai1,2,
- Peng Zhao3,
- Binkai Chi1,2,
- Lantian Wang1,2,
- Guohui Li7,
- Catherine C.L. Wong6,8,
- Yu Zhou5,
- Jinsong Li2,4,
- Caihong Yun3 and
- Hong Cheng1,2
- 1State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China;
- 2Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China;
- 3Department of Biophysics, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China;
- 4State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China;
- 5Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China;
- 6Center for Precision Medicine Multi-Omics Research, Peking University Health Science Center, Beijing 100191, China;
- 7Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China;
- 8State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
- Corresponding authors: hcheng{at}sibcb.ac.cn, yunch{at}hsc.pku.edu.cn, jsli{at}sibcb.ac.cn, yu.zhou{at}whu.edu.cn
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↵9 These authors contributed equally to this work.
Abstract
The exosome functions in the degradation of diverse RNA species, yet how it is negatively regulated remains largely unknown. Here, we show that NRDE2 forms a 1:1 complex with MTR4, a nuclear exosome cofactor critical for exosome recruitment, via a conserved MTR4-interacting domain (MID). Unexpectedly, NRDE2 mainly localizes in nuclear speckles, where it inhibits MTR4 recruitment and RNA degradation, and thereby ensures efficient mRNA nuclear export. Structural and biochemical data revealed that NRDE2 interacts with MTR4's key residues, locks MTR4 in a closed conformation, and inhibits MTR4 interaction with the exosome as well as proteins important for MTR4 recruitment, such as the cap-binding complex (CBC) and ZFC3H1. Functionally, MID deletion results in the loss of self-renewal of mouse embryonic stem cells. Together, our data pinpoint NRDE2 as a nuclear exosome negative regulator that ensures mRNA stability and nuclear export.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.322602.118.
- Received November 14, 2018.
- Accepted February 5, 2019.
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