The iRhom-ADAM17 complex

A central hub in inflammatory signalling

The iRhom-ADAM17 complex

Shedding describes the proteolytic release of biologically active ectodomains from membrane-bound proteins. The shedding complex with its core components, the transmembrane proteinases ADAM17 and the pseudoprotease iRhom, is an important release platform for many inflammatory mediators such as TNFα. It is therefore not surprising that dysregulation of the shedding activity of this complex can play a crucial role in diseases such as chronic inflammation.

Multilevel Regulation

The core iRhom-ADAM17 complex is formed in the ER to enable the transport of ADAM17 from the ER to the cell surface (1). In the Golgi, maturation of proADAM17 to mature ADAM17 takes place by cleavage of the prodomain promoted by furin-like protease (2). During the transport and at the cell surface, the shedding complex can interact with other proteins (3). Finally, the shedding process can be stimulated at the surface (4). ADAM17 thereby sheds its substrates, which can have different (patho)physiological effects (5) depending on the cellular context, iRhom interaction (iRhom1 vs. iRhom2) and substrate. Subsequently, the surface expression of ADAM17 is regulated internalisation (7). Overall, the iRhom-ADAM17 shedding complex is integrated in a larger protease web and signalling web (6).

Cluster Biology of Inflammation

Like the iRhom-ADAM17 complex, proteins are often part of larger functional complexes. When analysing these complexes, one has to take into account that these complexes are not static, but rather change dynamically depending on the cellular milieu and functional requirements. Therefore, we tend to consider the target proteins in our studies as parts of larger molecular clusters.