RESUMO
The rhomboid superfamily of transmembrane (TM) proteins includes intramembrane serine proteases and several classes of pseudoprotease. Rhomboid-like proteins occur widely across evolution and comprise biologically important regulators of fate of membrane proteins, influencing their proteolysis, trafficking, or degradation. In this review, we discuss how structural and mechanistic insights into the action of rhomboid proteases can inform on the mechanism of the pseudoproteases, and discuss the impact of structural understanding on the development of inhibitors and other chemical biology tools for these proteins. Development of modulators would be particularly relevant for the iRhoms, which are key regulators of ADAM17 and, hence, tumor necrosis factor (TNF) and epidermal growth factor receptor (EGFR) signaling, two medically important pathways.
Assuntos
Proteína ADAM17/metabolismo , Proteínas de Membrana/metabolismo , Proteólise , Transdução de Sinais/fisiologia , Proteína ADAM17/genética , Animais , Humanos , Proteínas de Membrana/genética , Transporte Proteico/fisiologia , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
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.
