iRHOM2-dependent regulation of ADAM17 in cutaneous disease and epidermal barrier function

Abstract

iRHOM2 is a highly conserved, catalytically inactive member of the Rhomboid family, which has recently been shown to regulate the maturation of the multi-substrate ectodomain sheddase enzyme ADAM17 (TACE) in macrophages. Dominant iRHOM2 mutations are the cause of the inherited cutaneous and oesophageal cancer-susceptibility syndrome tylosis with oesophageal cancer (TOC), suggesting a role for this protein in epithelial cells. Here, using tissues derived from TOC patients, we demonstrate that TOC-associated mutations in iRHOM2 cause an increase in the maturation and activity of ADAM17 in epidermal keratinocytes, resulting in significantly upregulated shedding of ADAM17 substrates, including EGF-family growth factors and pro-inflammatory cytokines. This activity is accompanied by increased EGFR activity, increased desmosome processing and the presence of immature epidermal desmosomes, upregulated epidermal transglutaminase activity and heightened resistance to Staphylococcal infection in TOC keratinocytes. Many of these features are consistent with the presence of a constitutive wound-healing-like phenotype in TOC epidermis, which may shed light on a novel pathway in skin repair, regeneration and inflammation.

Insights into Desmosome Biology from Inherited Human Skin Disease and Cardiocutaneous Syndromes

“…Strikingly, electron microscopy of the skin of TOC patients ( Figure 2B) revealed desmosomes lacking the electron-dense midlines seen in non-TOC skin (Brooke et al, 2014), consistent with desmosomes in a woundhealing state (Garrod, 2005). Furthermore, there appeared to be increased processing of DSG2 in TOC cutaneous keratinocytes (Brooke et al, 2014).…”

“…iRHOM2 (and its homologue iRHOM1) traffi c ADAM17 from the ER to the Golgi, where the inhibitory pro-domain is cleaved by furin (Adrain et al, 2012;McIlwain et al, 2012). A dramatic increase in the iRHOM2-mediated processing of ADAM17 in TOC cutaneous keratinocytes compared to that of control cells was observed (Brooke et al, 2014).…”

“…Furthermore, there appeared to be increased processing of DSG2 in TOC cutaneous keratinocytes (Brooke et al, 2014). DSG2 is reported to be expressed at lower levels in epidermis so other cadherins may also be affected.…”

“…In contrast, tylosis with oesophageal cancer (TOC) results in increased processing and activity of ADAM17 (Brooke et al, 2014). TOC patients suffer from PPK, follicular papules, oral keratosis, and up to a 95% lifetime risk of developing oesophageal cancer (Ellis et al, 1994;Hennies et al, 1995;Stevens et al, 1996).…”

“…DSG2 is reported to be expressed at lower levels in epidermis so other cadherins may also be affected. Alternatively, desmosomal remodelling may result from the increased EGFR signalling in TOC keratinocytes shown by increased migration, insensitivity to exogenous EGF (Blaydon et al, 2012) and increased shedding of EGFR ligands (Brooke et al, 2014). EGFR signalling results in phosphorylation of desmosomal cadherins followed by cleavage and endocytosis (Klessner et al, 2009;Lorch et al, 2004), and EGFR inhibition increases adhesion between cells (Lorch et al, 2004), so it is plausible that alterations in desmosomal composition may result from this altered EGFR signalling (Figure 2A).…”