Mammalian iRhoms have distinct physiological functions including an essential role in TACE regulation

Abstract

Loss of iRhom2, a catalytically inactive rhomboid-like protein, blocks maturation of TACE/ADAM17 in macrophages, resulting in defective shedding of the cytokine tumor necrosis factor. Apart from the resulting inflammatory defects, iRhom2-null mice appear normal: they do not show the several defects seen in TACE knockouts, suggesting that TACE maturation is independent of iRhom2 in cells other than macrophages. Here we show that the physiological role of iRhoms is much broader. iRhom1 knockout mice die within 6 weeks of birth. They show a severe phenotype, with defects in several tissues including highly penetrant brain haemorrhages. The non-overlapping phenotypes imply that iRhom 1 and 2 have distinct physiological roles, although at a cellular level both promote the maturation of TACE (but not other ADAM proteases). Both iRhoms are co-expressed in many contexts where TACE acts. We conclude that all TACE activity, constitutive and regulated, requires iRhom function. iRhoms are therefore essential and specific regulators of TACE activity, but our evidence also implies that they must have additional physiologically important clients.

iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling

“…A qPCR analysis of iRhom 1 and 2 transcripts in different tissues of wildtype mice demonstrated that both iRhoms were expressed across all tissues examined, with the exception of the brain, where iRhom1 was easily detected but levels of iRhom2 were very low ( Fig. 2 B and C) (biogps.org/#goto=genereport&id=217344) (30). Western blots of different parts of the brain of 8-wk-old iR1 −/− mice showed barely detectable mature ADAM17 in the cortex, cerebellum, brainstem, olfactory bulb, and hippocampus, in sharp contrast to wild-type mice ( Fig.…”

Inactive rhomboid proteins: New mechanisms with implications in health and disease

“…Given that some iRhom1 KO phenotypes are not explicable purely by ADAM17 biology [21] this could imply that additional iRhom clients exist.…”

“…Likewise, iRhom1 is expressed highly in many regions of the brain [20] potentially explaining the brain hemorrhages observed in ADAM17 KO mice and in one iRhom1 KO study [21,26].…”

“…iRhom2 KO mice respond less severely to sepsis, are protected from experimental arthritis, but exhibit increased sensitivity to Listeria infection, hallmarks of TNF biology [12, [22][23][24]. iRhom redundancy is illustrated by the fact that iRhom single KO mouse embryonic fibroblasts retain substantial ADAM17 activity, whereas ADAM17 is inactive in double knockout (DKO) cells [20,21]. The phenotype of iRhom1 KO mice and iRhom1/2 DKO mice themselves is controversial: a recent study reported that iRhom1 mice are aphenotypic [20], whereas a previous report found that iRhom1 KOs mice exhibited a cachectic phenotype, defects in several professional secretory tissues, and brain hemorrhages [21].…”

“…iRhom redundancy is illustrated by the fact that iRhom single KO mouse embryonic fibroblasts retain substantial ADAM17 activity, whereas ADAM17 is inactive in double knockout (DKO) cells [20,21]. The phenotype of iRhom1 KO mice and iRhom1/2 DKO mice themselves is controversial: a recent study reported that iRhom1 mice are aphenotypic [20], whereas a previous report found that iRhom1 KOs mice exhibited a cachectic phenotype, defects in several professional secretory tissues, and brain hemorrhages [21]. Concerning iRhom DKO mice, one study found that DKO embryos were lethal, whereas the later study reported perinatal lethality, similar to ADAM17 KO mice [20,21,25].…”