iTAP, a novel iRhom interactor, controls TNF secretion by policing the stability of iRhom/TACE
- Instituto Gulbenkian de Ciência, Portugal
- Trinity College, Dublin, Ireland
- Academy of Sciences of the Czech Republic, Czech Republic
- Albert Ludwigs Universitaet, Germany
- University of Vienna, Austria
- University of Edinburgh, United Kingdom
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
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
- Christopher G Burd, Yale School of Medicine, United States
Publication history
- Received: January 12, 2018
- Accepted: June 10, 2018
- Accepted Manuscript published: June 13, 2018 (version 1)
- Version of Record published: July 12, 2018 (version 2)
- 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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