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

Ioanna Oikonomidi, Emma Burbridge, Miguel Cavadas, Graeme Sullivan, Blanka Collis, Heike Naegele, Danielle Clancy, Jana Brezinova, Tianyi Hu, Andrea Bileck, Christopher Gerner, Alfonso Bolado, Alex von Kriegsheim, Seamus J Martin, Florian Steinberg, Kvido Strisovsky, Colin Adrain

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

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.

Original languageEnglish
JournaleLife
Volume7
DOIs
Publication statusPublished - 13 Jun 2018
Externally publishedYes

Bibliographical note

© 2018, Oikonomidi et al.

Keywords

  • ADAM17 Protein/genetics
  • Amino Acid Sequence
  • Animals
  • Carrier Proteins/genetics
  • Cell Line
  • Cytoskeletal Proteins/genetics
  • Endosomes/metabolism
  • Fibroblasts/cytology
  • Gene Expression Regulation
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Macrophages/cytology
  • Membrane Proteins/genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Primary Cell Culture
  • Protein Binding
  • Proteolysis
  • RAW 264.7 Cells
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Tumor Necrosis Factor-alpha/genetics

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