Abstract
The rhomboid family are evolutionary conserved intramembrane proteases. Their inactive members, iRhom in Drosophila melanogaster and iRhom1 and iRhom2 in mammals, lack the catalytic center and are hence labelled “inactive” rhomboid family members. In mammals, both iRhoms are involved in maturation and trafficking of the ubiquitous transmembrane protease a disintegrin and metalloprotease (ADAM) 17, which through cleaving many biologically active molecules has a critical role in tumor necrosis factor alpha (TNFα), epidermal growth factor receptor (EGFR), interleukin-6 (IL-6) and Notch signaling. Accordingly, with iRhom2 having a profound influence on ADAM17 activation and substrate specificity it regulates these signaling pathways. Moreover, iRhom2 has a role in the innate immune response to both RNA and DNA viruses and in regulation of keratin subtype expression in wound healing and cancer. Here we review the role of iRhom2 in immunity and disease, both dependent and independent of its regulation of ADAM17.
Highlights
Rhomboids are an evolutionarily conserved family of multi-span transmembrane proteins [1]
The underlying mechanism was related to the mutations activating iRhom2 which leads to increased ADAM17 maturation and activity in epidermal keratinocytes from Tylosis with oesophageal cancer (TOC) patients, which in turn increases shedding of TNFα, AR, TGFα and heparin-binding-EGF-like growth factor (HB-EGF) and enhances epidermal growth factor receptor (EGFR) phosphorylation [57]
IRhom2 has multiple functions during infections and diseases. iRhom2 was originally linked to ADAM17 maturation and activation and to functions related to ADAM17
Summary
Rhomboids are an evolutionarily conserved family of multi-span transmembrane proteins [1]. While structurally similar, are catalytically inactive and known as pseudoproteases These rhomboid pseudoproteases were found to be evolutionarily conserved indicating the presence of selective pressure despite absence of their proteolytic activity [6]. This alludes to functions beyond rhomboid catalytic activity that are important enough to be preserved. IRhoms 1 and 2, encoded by the genes Rhbdf 1 and 2, belong to the latter family of pseudoproteases They were named iRhoms to indicate their proteolytic inactivity while being part of the rhomboid family [7]. Both Drosophila and mammalian iRhoms bind their partner proteins in the ER. This review will focus on iRhom, both as a regulator of ADAM17 as well as its ADAM17-independent roles in immunity and disease
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