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iTAP, a novel iRhom interactor, controls TNF secretion by policing the stability of iRhom/TACE
I. Oikonomidi, E. Burbridge, M. Cavadas, G. Sullivan, B. Collis, H. Naegele, D. Clancy, J. Brezinova, T. Hu, A. Bileck, C. Gerner, A. Bolado, A. von Kriegsheim, SJ. Martin, F. Steinberg, K. Strisovsky, C. Adrain,
Language English Country England, Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
14/IA/2622
Science Foundation Ireland - Ireland
14-1289
Worldwide Cancer Research - United Kingdom
NLK
Directory of Open Access Journals
from 2013
Free Medical Journals
from 2012
PubMed Central
from 2012
Europe PubMed Central
from 2012
ProQuest Central
from 2012-01-01
Open Access Digital Library
from 2012-01-01
Open Access Digital Library
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Health & Medicine (ProQuest)
from 2012-01-01
ROAD: Directory of Open Access Scholarly Resources
from 2012
PubMed
29897333
DOI
10.7554/elife.35032
Knihovny.cz E-resources
- MeSH
- Cell Line MeSH
- Cytoskeletal Proteins genetics metabolism MeSH
- Endosomes metabolism MeSH
- Fibroblasts cytology metabolism MeSH
- HEK293 Cells MeSH
- HeLa Cells MeSH
- Humans MeSH
- Macrophages cytology metabolism MeSH
- Membrane Proteins genetics metabolism MeSH
- Mice, Inbred C57BL MeSH
- Mice, Knockout MeSH
- Mice MeSH
- Primary Cell Culture MeSH
- ADAM17 Protein genetics metabolism MeSH
- Proteolysis MeSH
- RAW 264.7 Cells MeSH
- Gene Expression Regulation MeSH
- Amino Acid Sequence MeSH
- Sequence Homology, Amino Acid MeSH
- Sequence Alignment MeSH
- Signal Transduction MeSH
- Tumor Necrosis Factor-alpha genetics metabolism MeSH
- Carrier Proteins genetics metabolism MeSH
- Protein Binding MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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 identified 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 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.
Institut für Analytische Chemie Universität Wien Vienna Austria
Membrane Traffic Lab Instituto Gulbenkian de Ciência Oeiras Portugal
References provided by Crossref.org
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