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Genes Dev. 2019 May 1;33(9-10):536-549. doi: 10.1101/gad.322602.118. Epub 2019 Mar 6.

NRDE2 negatively regulates exosome functions by inhibiting MTR4 recruitment and exosome interaction.

Wang J#1,2, Chen J#3, Wu G#1,2, Zhang H#2,4, Du X#5, Chen S1,2, Zhang L1,2, Wang K1,2, Fan J1,2, Gao S6, Wu X7, Zhang S3, Kuai B1,2, Zhao P3, Chi B1,2, Wang L1,2, Li G7, Wong CCL6,8, Zhou Y5, Li J2,4, Yun C3, Cheng H1,2.

Author information

1
State 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.
2
Shanghai 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.
3
Department of Biophysics, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
4
State 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.
5
Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China.
6
Center for Precision Medicine Multi-Omics Research, Peking University Health Science Center, Beijing 100191, China.
7
Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
8
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
#
Contributed equally

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.

KEYWORDS:

MTR4 recruitment; NRDE2; mRNA export; the nuclear exosome

PMID:
30842217
PMCID:
PMC6499326
[Available on 2019-11-01]
DOI:
10.1101/gad.322602.118
[Indexed for MEDLINE]

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