iRhom2

iRhom2 is a membrane protein of the rhomboid-like pseudoprotease family encoded by the human gene RHBDF2. Unlike active rhomboid proteases, iRhom2 lacks catalytic residues and functions as a regulatory adaptor. It is expressed in immune cells and epithelial tissues and localizes primarily to the endoplasmic reticulum and Golgi apparatus.

A well-characterized role of iRhom2 is the control of ADAM17 (a disintegrin and metalloprotease 17), a sheddase responsible for releasing cytokines and growth factors from the cell surface. iRhom2 promotes ADAM17 maturation and trafficking and thereby influences shedding of substrates such as tumor necrosis factor (TNF) and several epidermal growth factor receptor (EGFR) ligands. Through this axis, iRhom2 contributes to inflammatory signaling, innate immune responses, tissue repair, and EGFR-driven cell proliferation.

Genetic and experimental studies link iRhom2 to disease. Loss-of-function or knockout models show impaired TNF release and altered inflammatory responses, while gain-of-function mutations in RHBDF2 are associated with tylosis with oesophageal cancer, a syndrome featuring palmoplantar keratoderma and elevated esophageal cancer risk. Aberrant iRhom2 activity has also been implicated in chronic inflammatory conditions and certain cancers, making it a target of interest for therapeutic modulation of ADAM17-dependent pathways.

Mechanistic details of substrate selection, regulation by the N-terminal cytoplasmic domain, and broader roles in cell physiology remain active areas of research.