1. Biochemistry and Chemical Biology
  2. Cell Biology
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iTAP, a novel iRhom interactor, controls TNF secretion by policing the stability of iRhom/TACE

  1. Ioanna Oikonomidi
  2. Emma Burbridge
  3. Miguel Cavadas
  4. Graeme Sullivan
  5. Blanka Collis
  6. Heike Naegele
  7. Danielle Clancy
  8. Jana Brezinova
  9. Tianyi Hu
  10. Andrea Bileck
  11. Christopher Gerner
  12. Alfonso Bolado
  13. Alex von Kriegsheim
  14. Seamus J Martin
  15. Florian Steinberg
  16. Kvido Strisovsky
  17. Colin Adrain  Is a corresponding author
  1. Instituto Gulbenkian de Ciência, Portugal
  2. Trinity College, Dublin, Ireland
  3. Academy of Sciences of the Czech Republic, Czech Republic
  4. Albert Ludwigs Universitaet, Germany
  5. University of Vienna, Austria
  6. University of Edinburgh, United Kingdom
Research Article
  • Cited 23
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Cite this article as: eLife 2018;7:e35032 doi: 10.7554/eLife.35032

Abstract

The apical inflammatory cytokine TNF regulates numerous important biological processes including inflammation and cell death, and drives inflammatory diseases. TNF secretion requires TACE (also called ADAM17), which cleaves TNF from its transmembrane tether. The trafficking of TACE to the cell surface, and stimulation of its proteolytic activity, depends on membrane proteins, called iRhoms. To delineate how the TNF/TACE/iRhom axis is regulated, we performed an immunoprecipitation/mass spectrometry screen to identify iRhom-binding proteins. This identifies a novel protein, that we name iTAP (iRhom Tail-Associated Protein) that binds to iRhoms, enhancing the cell surface stability of iRhoms and TACE, preventing their degradation in lysosomes. Depleting iTAP in primary human macrophages profoundly impaired in TNF production and tissues from iTAP KO mice exhibit a pronounced depletion in active TACE levels. Our work identifies iTAP as a physiological regulator of TNF signalling and a novel target for the control of inflammation.

Data availability

We have provided the source data for all experiments that involved quantitative analyses.

Article and author information

Author details

  1. Ioanna Oikonomidi

    Membrane Traffic Lab, Instituto Gulbenkian de Ciência, Oeiras, Portugal
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1657-962X
  2. Emma Burbridge

    Membrane Traffic Lab, Instituto Gulbenkian de Ciência, Oeiras, Portugal
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4243-7193
  3. Miguel Cavadas

    Membrane Traffic Lab, Instituto Gulbenkian de Ciência, Oeiras, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  4. Graeme Sullivan

    Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  5. Blanka Collis

    Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  6. Heike Naegele

    Center for Biological Systems Analysis (ZBSA), Faculty of Biology,, Albert Ludwigs Universitaet, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Danielle Clancy

    Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  8. Jana Brezinova

    Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  9. Tianyi Hu

    Membrane Traffic Lab, Instituto Gulbenkian de Ciência, Oeiras, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  10. Andrea Bileck

    Institute of Analytical Chemistry, University of Vienna, Vienna, Austria
    Competing interests
    The authors declare that no competing interests exist.
  11. Christopher Gerner

    Institute for Analytical Chemistry, University of Vienna, Vienna, Austria
    Competing interests
    The authors declare that no competing interests exist.
  12. Alfonso Bolado

    Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Alex von Kriegsheim

    Edinburgh Cancer Research UK Centre Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Seamus J Martin

    Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  15. Florian Steinberg

    Center for Biological Systems Analysis (ZBSA), Faculty of Biology,, Albert Ludwigs Universitaet, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  16. Kvido Strisovsky

    Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3677-0907
  17. Colin Adrain

    Membrane Traffic Group, Instituto Gulbenkian de Ciência, Oeiras, Portugal
    For correspondence
    cadrain@igc.gulbenkian.pt
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7597-4393

Funding

Worldwide Cancer Research (14-1289)

  • Colin Adrain

Fundação para a Ciência e a Tecnologia (PTDC/BEX-BCM/3015/2014)

  • Colin Adrain

Fundação para a Ciência e a Tecnologia (SFRH/ BPD/117216/2016)

  • Miguel Cavadas

Fundação para a Ciência e a Tecnologia (91/BD/14)

  • Ioanna Oikonomidi

Fundação para a Ciência e a Tecnologia (SFRH/BCC/52507/2014)

  • Colin Adrain

Fundação Calouste Gulbenkian

  • Colin Adrain

Seventh Framework Programme (Marie Curie Career Integration Grant (project no. 618769)

  • Colin Adrain

The European Crohns and Colitis Organization

  • Colin Adrain

Science Foundation Ireland (14/IA/2622)

  • Seamus J Martin

European Molecular Biology Organization (Installation Grant no. 2329)

  • Kvido Strisovsky

Ministry of Education, Youth and Sports of the Czech Republic (LO1302)

  • Kvido Strisovsky

European Regional Development Fund (CZ.2.16/3.1.00/24016)

  • Kvido Strisovsky

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

Ethics

Animal experimentation: Experiments with mice were performed in accordance with protocols approved by the Ethics Committee of the Instituto Gulbenkian de Ciencia and the Portuguese National Entity (DGAV- Direcao Geral de Alimentacao e Veterinaria) and in accordance with the Portuguese (Decreto-Lei no. 113/2013) and European (directive 2010/63/EU) legislation related to housing, husbandry, and animal welfare.

Human subjects: Human bloods were obtained from healthy volunteers with informed consent, after review and approval by Trinity College Dublin's research ethics committee.

Reviewing Editor

  1. Christopher G Burd, Yale School of Medicine, United States

Publication history

  1. Received: January 12, 2018
  2. Accepted: June 10, 2018
  3. Accepted Manuscript published: June 13, 2018 (version 1)
  4. Version of Record published: July 12, 2018 (version 2)
  5. Version of Record updated: January 23, 2019 (version 3)

Copyright

© 2018, Oikonomidi 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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