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

Inflammation forms part of the body's defense system against pathogens, but if the system becomes faulty, it can cause problems linked to inflammatory and autoimmune diseases. Immune cells coordinate their activity using specific signaling molecules called cytokines. For example, the cytokine TNF is an important trigger of inflammation and is produced at the surface of immune cells. A specific enzyme called TACE is needed to release TNF, as well as other signaling molecules, including proteins that trigger healing. Previous work revealed that TACE works with proteins called iRhoms, which regulate its activity and help TACE to reach the surface of the cell to release TNF. To find out how, Oikonomidi et al. screened human cells to see what other proteins interact with iRhoms. The results revealed a new protein named iTAP, which is required to release TNF from the surface of cells. It also protects the TACE-iRhom complex from being destroyed by the cell’s waste disposal system. When iTAP was experimentally removed in human immune cells, the cells were unable to release TNF. Instead, iRhom and TACE travelled to the cell's garbage system, the lysosome, where the proteins were destroyed. Removing the iTAP gene in mice had the same effect, and the TACE-iRhom complex was no longer found on the surface of the cell, but instead degraded in lysosomes. This suggests that in healthy cells, the iTAP protein prevents the cell from destroying this protein complex. TNF controls many beneficial processes, including fighting infection and cancer. However, when the immune system releases too many cytokines, it can lead to inflammatory diseases or even cause cancer. Specific drugs that target TNF are not always effective administered on their own, and sometimes, patients stop responding to the drugs. Since the new protein iTAP works as a switch to turn TNF release on or off, it could provide a target for the development of new treatments.