iRHOM2 takes control of rheumatoid arthritis
Stefan F. Lichtenthaler
Stefan F. Lichtenthaler
View: Text | PDF
Commentary

iRHOM2 takes control of rheumatoid arthritis

Abstract

The cytokine TNF-α is a major drug target for rheumatoid arthritis, an inflammatory joint disorder. An alternative approach is to target the protease TNF-α convertase (TACE), which releases TNF-α from cells. However, because TACE cleaves other proteins involved in development and cancer, a tissue-specific inhibition of TACE in immune cells appears mandatory. In this issue of the JCI, Issuree et al. report that iRHOM2 is a TACE activator in immune cells. Loss of iRHOM2 largely protects mice from inflammatory arthritis, making iRHOM2 a potential drug target for this condition.

Authors

Stefan F. Lichtenthaler

×

Figure 1

Control of TACE maturation by iRHOM1 and iRHOM2.

Options: View larger image (or click on image) Download as PowerPoint
Control of TACE maturation by iRHOM1 and iRHOM2. (A) In wild-type cells,...
(A) In wild-type cells, iRHOM1 or iRHOM2 associate with immature TACE and promote TACE exit from the ER. In the Golgi, TACE undergoes maturation and activation and travels without the iRHOMs to the plasma membrane (PM), where it cleaves TNF-α and other TACE ligands, such as ligands for the EGFR. C5a receptor (C5aR) and Fcγ receptor (FcγR) activate iRHOM2 expression and TACE maturation in the immune system. (B) Immune cells lack significant iRHOM1 expression. Upon knockout of iRHOM2, TACE can no longer mature in immune cells. As a result, TNF-α is not cleaved, providing protection from TNF-α–dependent diseases, such as RA and sepsis. (C) iRHOM1 is expressed in nonimmune cells. In the absence of iRHOM2, iRHOM1 is sufficient for TACE activation, allowing TACE substrates to be cleaved normally in nonimmune cells.