Fig. 9.

The IRHD and the conserved motif iCERES are indispensable for ADAM17 maturation and activity. Wild type iRhoms bind immature ADAM17 in the ER and shuttle it to the Golgi by COP-II vesicle-dependent anterograde transport. In the Golgi ADAM17 maturation takes place. Afterwards, mature ADAM17 can reach the cell surface and can shed its substrates enabling a wide variety of different signalling pathways such as the TNFα and the EGFR pathways. When the structural integrity of the IRHD is compromised, the whole iRhom protein is functionally impaired regarding ADAM17 binding and transport. Moreover, misfolded iRhom is recognised by ER quality control and cannot enter ER exit sites (ERES). Instead, it undergoes rapid ERAD. In contrast, iRhoms tagged with the ER retention signal KDEL and iRhoms with disrupted iCERES can still bind immature ADAM17. They are not recognised by ER quality control and still enter ERES but cannot be transported into the Golgi