Format

Send to

Choose Destination
Elife. 2018 Jun 13;7. pii: e35032. doi: 10.7554/eLife.35032.

iTAP, a novel iRhom interactor, controls TNF secretion by policing the stability of iRhom/TACE.

Author information

1
Membrane Traffic Lab, Instituto Gulbenkian de Ciência, Oeiras, Portugal.
2
Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College Dublin, Dublin, Ireland.
3
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
4
Center for Biological Systems Analysis, Faculty of Biology, Albert Ludwigs Universitaet Freiburg, Freiburg, Germany.
5
Institut für Analytische Chemie, Universität Wien, Vienna, Austria.
6
Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, 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 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.

KEYWORDS:

TACE/ADAM17; Tumour Necrosis Factor (TNF); biochemistry; cell biology; chemical biology; human; iRhom2; inflammation; lysosome; mouse; vesicular trafficking; FRMD8

PMID:
29897333
PMCID:
PMC6042963
DOI:
10.7554/eLife.35032
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for eLife Sciences Publications, Ltd Icon for PubMed Central
Loading ...
Support Center