iRhom2 (inactive rhomboid protease homologue 2) (iRhom2)

iRhom2 is a catalytically inactive member of the rhomboid-like superfamily that acts as an essential cofactor and regulatory subunit for the metalloprotease TACE (ADAM17). It binds TACE throughout its lifecycle, promoting its exit from the endoplasmic reticulum (ER), maturation in the Golgi, and stabilization at the plasma membrane[1][2][3]. At the cell surface, iRhom2 phosphorylation (e.g., by ERK1/2) and subsequent 14-3-3 binding act as a molecular switch, licensing TACE to shed inflammatory cytokines (notably TNFα) and growth factors (e.g., ligands of the epidermal growth factor receptor)[1][2]. iRhom2 is particularly important in macrophages, where it is the sole regulator of TACE-dependent TNFα release, linking it to inflammation and innate immunity[1][2]. Loss of iRhom2 in mice leads to profound inflammatory defects, increased susceptibility to bacterial infection, and resistance to LPS-induced toxic shock and inflammatory arthritis[1][2]. iRhom2 also regulates innate immunity to DNA viruses by controlling ER-to-Golgi transport of the immune adaptor STING[1]. While iRhom2 is not a direct drug target in current clinical use, it represents a potential node for modulating cytokine and growth factor signaling in inflammatory and immune diseases[1][2].

Other names

iRhom2iRhom-2Rhbdf2 (gene)inactive rhomboid 2

Not directly applicable (iRhom2 is not an enzyme but a regulatory cofactor). Therapeutic modulation would aim to alter TACE activity at ER export, plasma membrane stabilization, or phosphorylation-dependent activation.