1. Cell Biology
  2. Immunology and Inflammation
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IRAK2 directs stimulus-dependent nuclear export of inflammatory mRNAs

  1. Hao Zhou
  2. Katarzyna Bulek
  3. Xiao Li
  4. Tomasz Herjan
  5. Minjia Yu
  6. Wen Qian
  7. Han Wang
  8. Gao Zhou
  9. Xing Chen
  10. Hui Yang
  11. Lingzi Hong
  12. Junjie Zhao
  13. Luke Qin
  14. Koichi Fukuda
  15. Annette Flotho
  16. Ji Gao
  17. Ashok Dongre
  18. Julie A Carman
  19. Zizhen Kang
  20. Bing Su
  21. Timothy S Kern
  22. Jonathan D Smith
  23. Thomas A Hamilton
  24. Frauke Melchior
  25. Paul L Fox
  26. Xiaoxia Li  Is a corresponding author
  1. Cleveland Clinic, United States
  2. Stanford University School of Medicine, United States
  3. Zentrum für Molekulare Biologie der Universität Heidelberg, Germany
  4. Bristol-Myers Squibb, United States
  5. Shanghai Jiao Tong University School of Medicine, China
  6. Case Western Reserve University, United States
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Cite this article as: eLife 2017;6:e29630 doi: 10.7554/eLife.29630

Abstract

Expression of inflammatory genes is determined in part by post-transcriptional regulation of mRNA metabolism but how stimulus- and transcript-dependent nuclear export influence is poorly understood. Here we report a novel pathway in which LPS/TLR4 engagement promotes nuclear localization of IRAK2 to facilitate nuclear export of a specific subset of inflammation related mRNAs for translation in murine macrophages. IRAK2 kinase activity is required for LPS-induced RanBP2-mediated IRAK2 sumoylation and subsequent nuclear translocation. Array analysis showed that an SRSF1 binding motif is enriched in mRNAs dependent on IRAK2 for nuclear export. Nuclear IRAK2 phosphorylates SRSF1 to reduce its binding to target mRNAs, which promotes the RNA binding of the nuclear export adaptor ALYREF and nuclear export receptor Nxf1 loading for the export of the mRNAs. In summary, LPS activates a nuclear function of IRAK2 that facilitates the assembly of nuclear export machinery to export selected inflammatory mRNAs to the cytoplasm for translation.

Article and author information

Author details

  1. Hao Zhou

    Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Katarzyna Bulek

    Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Xiao Li

    Department of Genetics, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Tomasz Herjan

    Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Minjia Yu

    Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Wen Qian

    Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Han Wang

    Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Gao Zhou

    Department of Genetics, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Xing Chen

    Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Hui Yang

    Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Lingzi Hong

    Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Junjie Zhao

    Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Luke Qin

    Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Koichi Fukuda

    Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Annette Flotho

    Zentrum für Molekulare Biologie der Universität Heidelberg, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  16. Ji Gao

    Discovery Biology, Bristol-Myers Squibb, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Ashok Dongre

    Discovery Biology, Bristol-Myers Squibb, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Julie A Carman

    Discovery Biology, Bristol-Myers Squibb, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Zizhen Kang

    Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Bing Su

    Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  21. Timothy S Kern

    School of Medicine, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  22. Jonathan D Smith

    Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  23. Thomas A Hamilton

    Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  24. Frauke Melchior

    Zentrum für Molekulare Biologie der Universität Heidelberg, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9546-8797
  25. Paul L Fox

    Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  26. Xiaoxia Li

    Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
    For correspondence
    lix@ccf.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4872-9525

Funding

National Multiple Sclerosis Society (RG5130A2/1)

  • Xiaoxia Li

National Institutes of Health (2PO1HL029582)

  • Xiaoxia Li

American Diabetes Association (Postdoctoral Research Fellow Award,1-16-PDF-138)

  • Hao Zhou

National Science Centre, Poland (2015/19/B/NZ6/01578)

  • Katarzyna Bulek

National Institutes of Health (PO1CA062220)

  • Xiaoxia Li

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All procedures using animals were approved by the Cleveland Clinic Institutional Animal Care and Use Committee (Protocol Number: 2014-1229 and 2017-1814) .

Reviewing Editor

  1. Feng Shao, National Institute of Biological Sciences, China

Publication history

  1. Received: June 15, 2017
  2. Accepted: October 6, 2017
  3. Accepted Manuscript published: October 9, 2017 (version 1)
  4. Version of Record published: November 7, 2017 (version 2)

Copyright

© 2017, Zhou et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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