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.
- MeSH
- buněčné linie MeSH
- cytoskeletální proteiny genetika metabolismus MeSH
- endozomy metabolismus MeSH
- fibroblasty cytologie metabolismus MeSH
- HEK293 buňky MeSH
- HeLa buňky MeSH
- lidé MeSH
- makrofágy cytologie metabolismus MeSH
- membránové proteiny genetika metabolismus MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- primární buněčná kultura MeSH
- protein ADAM17 genetika metabolismus MeSH
- proteolýza MeSH
- RAW 264.7 buňky MeSH
- regulace genové exprese MeSH
- sekvence aminokyselin MeSH
- sekvenční homologie aminokyselin MeSH
- sekvenční seřazení MeSH
- signální transdukce MeSH
- TNF-alfa genetika metabolismus MeSH
- transportní proteiny genetika metabolismus MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
